Conditions: Lung Cancer, Non-Small Cell Metastatic Squamous Cell Carcinoma Metastatic Non-Squamous Cell Carcinoma
Keywords: NSCLC Lung Cancer Metastatic Squamous Non-Small Cell Lung Cancer Metastatic Non-Squamous Cell Lung Cancer
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 24
Healthy volunteers: no

Brief summary:
A Phase 1/2, Open-Label Study of ADXS-503 Alone and in Combination with Pembrolizumab in Subjects with Metastatic Squamous or Non-Squamous Non-Small Cell Lung Cancer

Detailed description:
To evaluate the safety and tolerability of ADXS-503, administered as monotherapy in Part A and in combination with pembrolizumab in Part B, and to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD). As well, to characterize the preliminary anti-tumor activity of ADXS-503, administered in combination with pembrolizumab in Part C, per RECIST v1.1.

Arms:
arm 1: Enroll subjects with metastatic squamous or non-squamous NSCLC who have become refractory or intolerant to standard therapy. ADXS-503 monotherapy will be evaluated at 2 planned escalating dose levels:

* Dose level 1: 1e8 CFU of ADXS-503, IV, every 3 weeks until disease progression, unacceptable toxicity, or another treatment discontinuation criterion is met.
* Dose level 2: 5e8 CFU of ADXS-503, IV, every 3 weeks until disease progression, unacceptable toxicity, or another treatment discontinuation criterion is met. arm 2: Enroll subjects with metastatic squamous or non-squamous NSCLC. ADXS-503 will be evaluated at 2 planned escalating dose levels in combination with a fixed dose of pembrolizumab:

* Dose level 1: 1e8 CFU of ADXS-503 + 200 mg of pembrolizumab, IV, every 3 weeks for up to 2 years or until disease progression, unacceptable toxicity, or another treatment discontinuation criterion is met.
* Dose level 2: 5e8 CFU of ADXS-503 + 200 mg of pembrolizumab, IV, every 3 weeks for up to 2 years or until disease progression, unacceptable toxicity, or another treatment discontinuation criterion is met. (recruitment is on hold for this arm) arm 3: Enroll subjects with metastatic squamous or non-squamous NSCLC.

1e8 CFU of ADXS-503 + 200 mg of pembrolizumab, IV, every 3 weeks for up to 2 years or until disease progression, unacceptable toxicity, or another treatment discontinuation criterion is met.

Interventions: intervention 1: ADXS-503 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: A live attenuated Listeria monocytogenes (Lm)-based immunotherapy bioengineered to elicit T cell responses against shared tumor antigens commonly found in patients with squamous and non-squamous NSCLC. intervention 2: a programmed death receptor-1 (PD-1)- blocking antibody.

Protocol document:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
 
 
Protocol ADXS-503-101 
 
1 
 
                                                                                                                  
 
 
Title Page 
A Phase 1/2, Open-Label Study of ADXS-503 Alone and in Combination with 
Pembrolizumab in Subjects with Metastatic Squamous or Non-Squamous 
Non-Small Cell Lung Cancer 
 
Protocol Number: ADXS-503-101 
Compound Number/ Name: ADXS-503 
Sponsor Name and Legal Registered Address: 
Advaxis, Inc. 
9 Deer Park Drive, Suite K-1 
Monmouth Junction, NJ 08852 
Regulatory Agency Identifying Number(s): IND #: 018284 
 
This study will be conducted under Food & Drug Administration IND regulations (CFR Part 
312). 
 
 
Protocol Version and Date:  
Original Protocol, Version 1.0 dated 21-JUN-2018 
Amendment # 1, Version 2.0 dated 06-AUG-2018  
Amendment # 2, Version 3.0 dated 17-SEP-2018 
Amendment # 3, Version 4.0 dated 14-OCT-2019 
Amendment #4, Version 5.0, dated 19-JUN-2021 
(see Section 13 for summary of protocol changes) 
 
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, Inc.  
 


CONFIDENTIAL 
 
 
Protocol ADXS-503-101 
 
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PROTOCOL APPROVAL 
 
A Phase 1/2, Open-Label Study of ADXS-503 Alone and in Combination with 
Pembrolizumab in Subjects with Metastatic Squamous or Non-Squamous 
Non-Small Cell Lung Cancer  
Protocol Number: ADXS-503-101 
Protocol Version and Date: 
 
Original protocol, Version 1.0 dated 21-JUN-2018 
 
Amendment # 1, Version 2.0 dated 06-AUG-2018  
 
Amendment # 2, Version 3.0 dated 17-SEP-2018 
 
Amendment # 3, Version 4.0 dated 14-OCT-2019 
 
Amendment #4, Version 5.0 dated 19-JUN-2021 
 
 
 
 
 _____________________________________  
 _________________________ 
Signature 
Date 
 
 
 
Andres A Gutierrez, MD, PhD 
Chief Medical Officer EVP- Advaxis, Inc. 
 
 
 
 
June 22, 2021


CONFIDENTIAL 
 
 
Protocol ADXS-503-101 
 
3 
 
INVESTIGATOR SIGNATURE PAGE 
A Phase 1/2, Open-Label Study of ADXS-503 Alone and in Combination with 
Pembrolizumab in Subjects with Metastatic Squamous or Non-Squamous Non-Small Cell 
Lung Cancer  
Protocol Number: ADXS-503-101 
Protocol Version and Date: 
 
Original protocol, Version 1.0 dated 21-JUN-2018 
 
Amendment # 1, Version 2.0 dated 06-AUG-2018  
 
Amendment # 2, Version 3.0 dated 17-SEP-2018  
 
Amendment # 3, Version 4.0 dated 14-OCT-2019 
 
Amendment #4, Version 5.0 dated 19-JUN-2021 
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 (GCP), International 
Conference on Harmonisation (ICH) Guidelines, the Declaration of Helsinki, and local ethical 
and legal requirements. 
 
Investigator Name:  
 
 _____________________________________  
 _________________________ 
Signature 
Date 
 
_____________________________________ 
Site #:  __________ 
Printed Name 
 
 


CONFIDENTIAL 
 
 
Protocol ADXS-503-101 
 
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Table of Contents 
1. 
Trial Summary ................................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
2. 
Schedule of Activities (SoA) .........................................................................................17 
2.1. 
Safety Phase Part A: ADXS-503 Monotherapy ..............................................................17 
2.2. 
Part B (Safety & Efficacy Phases) and Part C: ADXS-503 + 
Pembrolizumab ...............................................................................................................21 
3. 
Introduction ...................................................................................................................25 
3.1. 
Background on Non-Small Cell Lung Cancer ................................................................25 
3.1.1. 
Mutational Burden in Non-Small Cell Lung Cancer ......................................................26 
3.2. 
Targeting Driver Mutations in Metastatic Non-Small Cell Lung 
Cancer .............................................................................................................................28 
3.3. 
Immunotherapy in Metastatic Non-Small Cell Lung Cancer .........................................28 
3.3.1. 
Immune Checkpoint Inhibitors in First-Line Metastatic Non-
Small Cell Lung Cancer ..................................................................................................29 
3.3.2. 
The Unmet Need for New Immunotherapies to Treat Patients 
with Metastatic Non-Small Cell Lung Cancer ................................................................31 
3.4. 
Overview of ADXS-503 .................................................................................................32 
3.4.1. 
Description of ADXS-503 Construct ..............................................................................33 
3.4.2. 
Mechanism of Action ......................................................................................................33 
3.4.3. 
Nonclinical Studies with ADXS-503 ..............................................................................35 
3.4.4. 
Clinical Experience with ADXS-503..............................................................................36 
3.4.5. 
Combination of Lm-Based Immunotherapy with an Immune 
Checkpoint Inhibitor .......................................................................................................41 
3.5. 
Study Rationale and Selected Patient Population ...........................................................43 
3.6. 
Overall Benefit/ Risk Assessment ..................................................................................47 
3.6.1. 
Potential Benefits ............................................................................................................47 
3.6.2. 
Potential Risks ................................................................................................................47 
4. 
Study Objectives and Endpoints .................................................................................51 
5. 
Investigational Plan ......................................................................................................53 
5.1. 
Study Design ...................................................................................................................53 
5.1.1. 
Safety Phase ....................................................................................................................57 
5.1.2. 
Efficacy Phase .................................................................................................................60 
5.1.3. 
Summary of Study Procedures/Assessments ..................................................................61 
5.2. 
Scientific Rationale for Study Design ............................................................................65 
5.2.1. 
Rationale for Starting Dose .............................................................................................65 
5.2.2. 
Rationale for 3+3 Dose Escalation/De-Escalation and Dose-
Expansion Design ...........................................................................................................65 
5.3. 
Number of Subjects Enrolled ..........................................................................................66 
5.4. 
End of Study Definition ..................................................................................................66 
6. 
Study Population ...........................................................................................................66 
6.1. 
Inclusion Criteria ............................................................................................................66 


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Protocol ADXS-503-101 
 
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6.2. 
Exclusion Criteria ...........................................................................................................71 
6.3. 
Lifestyle Restriction ........................................................................................................74 
6.4. 
Screen Failures ................................................................................................................74 
7. 
Treatments .....................................................................................................................74 
7.1. 
Treatments Administered ................................................................................................75 
7.1.1. 
ADXS-503 Monotherapy (Part A) ..................................................................................75 
7.1.2. 
ADXS-503 + Pembrolizumab (Part B Dose-Escalation and Dose-
Expansion) ......................................................................................................................76 
7.1.3. 
ADXS-503 + Pembrolizumab (Part C) ...........................................................................79 
7.2. 
Preparation/ Handling/ Storage/ Accountability .............................................................81 
7.3. 
Treatment Compliance ....................................................................................................82 
7.4. 
Method of Treatment Assignment ..................................................................................82 
7.5. 
Blinding ..........................................................................................................................82 
7.6. 
Treatment Modification and Discontinuation Guidelines for 
Toxicity ...........................................................................................................................83 
7.6.1. 
ADXS-503: Treatment Modification and Discontinuation 
Guidelines .......................................................................................................................83 
7.6.2. 
Pembrolizumab: Treatment Modification and Discontinuation 
Guidelines .......................................................................................................................85 
7.7. 
Concomitant Therapy .....................................................................................................87 
7.7.1. 
Concomitant Medications ...............................................................................................87 
7.7.2. 
Prohibited Medications/ Therapy ....................................................................................88 
7.7.3. 
Major and Minor Surgeries and ADXS-503 Treatment .................................................89 
7.8. 
Treatment after the End of the Study ..............................................................................89 
8. 
Discontinuation/ Withdrawal Criteria ........................................................................89 
8.1. 
Discontinuation of Study Treatment ...............................................................................89 
8.1.1. 
Treatment after Initial Evidence of Radiologic Disease 
Progression ......................................................................................................................90 
8.1.2. 
Treatment/ Enrollment Stopping Rules ..........................................................................91 
8.2. 
Discontinuation from the Study ......................................................................................92 
8.2.1. 
Withdrawal from the Study .............................................................................................92 
8.2.2. 
Lost to Follow-Up ...........................................................................................................93 
9. 
Study Assessments and Procedures.............................................................................93 
9.1. 
Safety Assessments .........................................................................................................94 
9.1.1. 
Physical Examinations ....................................................................................................94 
9.1.2. 
Vital Sign Measurements ................................................................................................94 
9.1.3. 
Performance Status Monitoring ......................................................................................95 
9.1.4. 
Clinical Safety Laboratory Assessments ........................................................................95 
9.1.5. 
Assessment and Reporting of Adverse Events ...............................................................95 
9.1.6. 
Dose Limiting Toxicity Criteria ......................................................................................98 
9.2. 
Clinical Safety Management .........................................................................................100 
9.2.1. 
ADXS-503 Treatment and Lm Management Guidelines ..............................................100 
9.2.2. 
Supportive Care Guidelines for ADXS-503 and Pembrolizumab ................................104 
9.3. 
Treatment of Overdose .................................................................................................105 


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9.4. 
Efficacy Assessments ...................................................................................................106 
9.4.1. 
Tumor Response-Based Assessments ...........................................................................106 
9.4.2. 
Survival Assessments....................................................................................................108 
9.5. 
Biomarker Assessments ................................................................................................108 
9.5.1. 
Biomarker Evaluation in Part A and Part B ..................................................................110 
9.6. 
Pharmacokinetic Assessments ......................................................................................110 
9.7. 
Pharmacodynamic Assessments ...................................................................................111 
9.8. 
Pharmacogenomic Assessments ...................................................................................111 
9.9. 
Health Economics OR Medical Resource Utilization and Health 
Economic Assessments .................................................................................................111 
10. 
Statistical Considerations ...........................................................................................111 
10.1. 
Sample Size Determination ..........................................................................................111 
10.2. 
Populations for Statistical Analyses .............................................................................112 
10.3. 
Statistical Analyses .......................................................................................................113 
10.3.1. Analysis of Safety .........................................................................................................113 
10.3.2. Analysis of Efficacy ......................................................................................................113 
10.3.3. Biomarker Analyses ......................................................................................................115 
10.3.4. Interim Analyses ...........................................................................................................116 
11. 
Regulatory ...................................................................................................................117 
12. 
References ....................................................................................................................118 
13. 
Summary of Changes Within Protocol Amendment 4 ............................................123 
14. 
Appendices ...................................................................................................................133 
  
List of Appendices 
Appendix 1 
Abbreviations and Terms ................................................................................ 134 
Appendix 2 
Clinical Laboratory Tests ................................................................................ 139 
Appendix 3 
Study Governance Considerations .................................................................. 141 
Appendix 4 
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up and Reporting ......................................................................................................................... 144 
Appendix 5 
Contraceptive Guidance and Collection of Pregnancy Information ............... 149 
Appendix 6 
Recommended Management Guidelines for Infusion Reactions .................... 152 
Appendix 7 
Grading and Management Guidelines for Acute Hypotension, Hypoxia, 
Encephalopathy, Organ Toxicity, Fever and Constitutional Symptoms..................................... 153 
Appendix 8 
General Approach for Managing Immune-Related Adverse Events Associated 
with ADXS-503  ......................................................................................................................... 164 
Appendix 9 
Guidelines to Manage Immune-Related Adverse Events Associated with 
Pembrolizumab  ......................................................................................................................... 165 
Appendix 10 
Assessment of Disease .................................................................................... 167 


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Protocol ADXS-503-101 
 
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Appendix 11 
ECOG Performance Status .............................................................................. 170 
List of In-Text Tables 
Table 1: Treatment-Related Adverse Events Reported ≥5% with ADXS11-001 Monotherapy in 
Advaxis Sponsored Trials ............................................................................................................. 38 
Table 2: Treatment-Related Adverse Events, All Treated ............................................................ 40 
Table 3: Treatment-Related Adverse Events >10% with ADXS-PSA Alone (Part A) and in 
Combination with Pembrolizumab (Part B) in Metastatic Castrate-Resistant Prostate Cancer 
(mCRPC)....................................................................................................................................... 42 
Table 4: Organ Function Requirements for Study Inclusion ........................................................ 70 
Table 5: Treatment in Part A: ADXS-503 Monotherapy .............................................................. 75 
Table 6: Treatment in Part B: ADXS-503 + Pembrolizumab ....................................................... 77 
Table 7: Treatment in Part C: ADXS-503 + Pembrolizumab ....................................................... 79 
Table 8: Treatment Modifications/Discontinuation for ADXS-503-Related Toxicity ................. 84 
Table 9: Treatment Modifications/ Discontinuation for Pembrolizumab-Related Toxicity ......... 85 
Table 10: Populations for Statistical Analysis ............................................................................ 112 
List of In-Text Figures 
Figure 1. Study Design ................................................................................................................. 15 
Figure 2. Driver mutations in non-small cell lung cancer. ........................................................... 27 
Figure 3. Lm-based immunotherapies induce expression of PD-L1 on tumor cells and tumor-
infiltrating macrophages in a HPV+ murine tumor model. .......................................................... 35 
Figure 4. Both ADXS-503 and ADXS-Kras G12D, an Lm-based vector targeting a single Kras 
hotspot mutation, significantly inhibit the growth of CT26 tumors. ............................................ 36 
 


CONFIDENTIAL 
 
 
Protocol ADXS-503-101 
 
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1. 
Trial Summary 
1.1. 
Synopsis 
Study Title 
A Phase 1/2, Open-Label Study of ADXS-503 Alone and in Combination with Pembrolizumab 
in Subjects with Metastatic Squamous or Non-Squamous Non-Small Cell Lung Cancer 
Trial Phase 
Phase 1/2 
Clinical Indication 
Non-Small Cell Lung Cancer 
Trial Type 
Interventional, Simon’s Two-stage design for Part B 
Interventions 
• 
ADXS-503: a live attenuated Listeria monocytogenes (Lm)-based immunotherapy 
bioengineered to elicit potent T cell responses against 22 tumor antigens that include           
1) 11 peptide antigens derived from frequently occurring and commonly shared hotspot 
mutations in patients with squamous and non-squamous NSCLC and 2) 11 peptide antigens 
derived from sequence-optimized tumor-associated antigens (TAAs) that are differentially 
expressed or overexpressed in NSCLC tumors. 
• 
Pembrolizumab: a programed death receptor-1 (PD-1)- blocking antibody. 
Type of control 
None 
Route of administration 
Intravenous 
Trial Blinding 
Unblinded, Open-label 
Estimated duration of trial The sponsor estimates that for the duration of patient participation, the trial will require 
approximately 3 years from the time the first subject signs the informed consent until the last 
subject’s last visit (which includes therapy for up to 2 years, plus survival and Lm surveillance 
follow-up for 1 year after subject’s last visit or upon discontinuation from therapy with ADXS-
503, whichever comes first). Approximate duration of trial: 4 years.  
Study Phases/ Parts 
 Safety phase 
• 
Part A: ADXS-503 monotherapy dose escalation 
• 
Part B: ADXS-503 + pembrolizumab dose escalation 
 Efficacy phase 
• 
Part B: ADXS-503 + pembrolizumab dose expansion 
• 
Part C: ADXS-503 + pembrolizumab 
See 
Figure 1 for a schematic of the study design. 
Subject Population 
Safety phase (Part A and Part B):  
 
Part A will enroll subjects with metastatic squamous or non-squamous NSCLC who have 
become refractory or intolerant to standard therapy. To be eligible for Part A, subjects must have 
previously received, and then progressed or been intolerant to up to 3 lines of prior therapy in the 
metastatic setting, including approved chemotherapy, targeted therapy, immunotherapy and 
antibody therapy, if eligible. Subjects will be eligible for Part A irrespective of PD-L1 expression 
or EGFR or ALK mutation status. However, subjects with an EGFR sensitizing mutation or ALK 
translocation must have received and then progressed or been intolerant to at least 1 prior line of 
approved targeted therapy to be eligible for Part A. 
Part B dose-escalation will enroll subjects with metastatic squamous or non-squamous NSCLC 
who meet the following criteria: 
• 
Are undergoing treatment with pembrolizumab monotherapy as last therapy for metastatic 
NSCLC 
 
                                        
 
                                                 
         
 
                                                
                          
 
                                   
                                             
                                             
 
                                        
 
                                                            
                                                      
                                                          
                                                                
                                                  
 
                                                              
                                     


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Protocol ADXS-503-101 
 
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OR 
• 
Are undergoing combination therapy with pembrolizumab plus platinum-based 
chemotherapy as last treatment 
                                                                               OR 
• 
Are receiving pembrolizumab + pemetrexed as maintenance therapy, as last treatment after 
completing treatment with pembrolizumab plus platinum-based chemotherapy  
• 
The subject’s most recent tumor assessment is consistent with progressive disease (PD) 
according to RECIST v1.1 
• 
There is no evidence of rapid disease progression or clinical deterioration that would 
preclude continuation of pembrolizumab for up to 12 weeks before ADXS-503 is added-on. 
• 
In Part B, subjects must receive the first dose of ADXS-503 within 12 weeks of the initial 
tumor assessment showing PD (while on last treatment with pembrolizumab monotherapy or 
pembrolizumab + platinum-based chemotherapy or pembrolizumab + pemetrexed as 
maintenance therapy). ADXS-503 will be administered as add-on treatment to the ongoing 
pembrolizumab therapy.  
Subjects who are receiving pembrolizumab in combination with platinum-based chemotherapy or 
pembrolizumab with pemetrexed as maintenance therapy, will continue on pembrolizumab 
monotherapy every 3 weeks per schedule while other drugs are washed-out for 3 weeks. Subject 
must consent to allow the acquisition of fresh or archival formalin-fixed paraffin embedded 
(FFPE) tumor tissue, either a block or unstained slides along with a matching blood at baseline, 
for performance of sequencing analysis. 
Efficacy phase (Part B expansion and Part C): 
Part B expansion will enroll subjects with metastatic squamous or non-squamous NSCLC who 
meet the same criteria as Part B dose escalation mentioned above. Based on Stage I of Simon’s 
Two-stage design, 18 patients will be accrued in this study arm. Sponsor may decide to accrue 
additional 25 subjects for a total of 43 patients in Stage II. Accrual of patients to Part B dose 
level 2 (ADXS-503 at 5x108 CFU in combination with 200 mg pembrolizumab) is pending 
Sponsor decision to commence 
Part C will enroll subjects with metastatic squamous or non-squamous NSCLC who have 
received no prior systemic treatment in the metastatic setting, and who will be treated in 
accordance with the approved Product Label for pembrolizumab monotherapy for first-line 
treatment. Clinical site must provide documentation of tumor PD-L1 expression and EGFR 
mutation and/or ALK translocation status as evaluated by FDA-approved tests in all patients. 
Baseline tumor samples must express PD-L1 [TPS (Tumor Proportion Score) ≥1%] as 
determined by an FDA-approved test at a local laboratory facility, with no EGFR or ALK 
genomic tumor aberrations for subjects to be eligible for Part C. Subject must consent to allow 
the acquisition of fresh or archival FFPE tumor tissue, either a block or unstained slides along 
with a matching blood at baseline, for performance of sequencing analysis. 
Study Objectives 
Primary 
• 
To evaluate the safety and tolerability of ADXS-503 monotherapy in Part A and ADXS-503 
+ pembrolizumab in Part B, and to determine the MTD or MAD. 
• 
To characterize the preliminary anti-tumor activity of ADXS-503 + pembrolizumab in Part B 
and Part C per RECIST v1.1. 
Secondary 
• 
To characterize the preliminary anti-tumor activity of ADXS-503 monotherapy in dose 
escalation Part A and ADXS-503 + pembrolizumab in Part B per RECIST v1.1.  
• 
To determine PFS and PFS rate at 12 months per RECIST v1.1, for subjects treated with 
ADXS-503 monotherapy in Part A and ADXS-503 + pembrolizumab in Part B and Part C. 
• 
To determine OS and 6- and 12-month milestone OS rates for subjects treated with ADXS-


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Protocol ADXS-503-101 
 
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503 monotherapy in Part A and ADXS-503 + pembrolizumab in Part B and Part C. 
• 
To evaluate the safety and tolerability of ADXS-503 + pembrolizumab in Part C. 
Exploratory 
• 
To characterize the preliminary anti-tumor activity, PFS and PFS rate at 12 months per 
iRECIST for subjects treated with ADXS-503 monotherapy in Part A, and ADXS-503 + 
pembrolizumab in Part B and Part C. 
• 
To evaluate correlates of immune response and biomarkers in peripheral blood and biopsy 
samples pre- and on-treatment in Part A, Part B and Part C. 
Treatment Groups 
Safety Phase  
• 
Part A: ADXS-503 monotherapy dose escalation (3+3 design) 
ADXS-503 monotherapy will be evaluated at 2 planned escalating dose levels: 
o 
Dose level 1:  1x108 CFU of ADXS-503, IV, every 3 weeks until disease 
progression, unacceptable toxicity, or another treatment discontinuation criterion 
is met. 
o 
Dose level 2:  5x108 CFU of ADXS-503, IV, every 3 weeks until disease 
progression, unacceptable toxicity, or another treatment discontinuation criterion 
is met. 
• 
Part B: ADXS-503 + pembrolizumab dose escalation (3+3 design) 
ADXS-503 will be evaluated at 2 planned escalating dose levels in combination with a fixed 
dose of pembrolizumab (with second dose level commencing upon Sponsor’s decision): 
o 
Dose level 1:  1x108 CFU of ADXS-503 + 200 mg of pembrolizumab, IV, every 
3 weeks for up to 2 years or until disease progression, unacceptable toxicity, or 
another treatment discontinuation criterion is met. Upon Investigator assessment, 
Investigator could shift the schedule of therapy with 1x108 CFU of ADXS-503 + 
200 mg of pembrolizumab, IV, from every 3 weeks to every 6 weeks after the 
first year of study treatment. 
o 
Dose level 2:  5x108 CFU of ADXS-503 + 200 mg of pembrolizumab, IV, every 
3 weeks for up to 2 years or until disease progression, unacceptable toxicity, or 
another treatment discontinuation criterion is met. Upon Investigator assessment, 
Investigator could shift the schedule of therapy with 1x108 CFU of ADXS-503 + 
200 mg of pembrolizumab, IV, from every 3 weeks to every 6 weeks after the 
first year of study treatment. 
Efficacy Phase 
• 
Part B-Expansion: ADXS-503 + pembrolizumab dose expansion (Simon’s Two-stage 
design) 
o 
Dose-expansion (DL-1): 1x108 CFU of ADXS-503 + 200 mg of pembrolizumab, 
IV, every 3 weeks for up to 2 years or until disease progression, unacceptable 
toxicity, or another treatment discontinuation criterion is met.  Upon Investigator 
assessment, Investigator could shift the schedule of therapy with 1x108 CFU of 
ADXS-503 + 200 mg of pembrolizumab, IV, from every 3 weeks to every 6 
weeks after the first year of study treatment. 
• 
Part C: ADXS-503 + pembrolizumab 
o 
1x108 CFU of ADXS-503 + 200 mg of pembrolizumab, IV, every 3 weeks for up 
to 2 years or until disease progression, unacceptable toxicity, or another treatment 
discontinuation criterion is met. Upon Investigator assessment, Investigator could 
shift the schedule of therapy with 1x108 CFU of ADXS-503 + 200 mg of 
pembrolizumab, IV, from every 3 weeks to every 6 weeks after the first year of 
study treatment. 
Number of trial subjects 
Safety phase: Up to approximately 24 subjects will be enrolled in the safety phase; up to 12 
subjects in Part A and up to 12 subjects in Part B based on a 3+3 dose escalation design at 2 


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Protocol ADXS-503-101 
 
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escalating dose levels. Up to approximately 25 subjects may also be enrolled in a Part A 
expansion cohort. 
 
Efficacy phase: Up to approximately 165 subjects may be enrolled in the efficacy phase (Part B-
expansion and Part C combined). Up to 43 subjects may be enrolled in Part B expansion of DL1 
in the Simon’s Two-stage study cohort (S1 [n=18], and S2 [n= 25]) and up to a total of 140 
thereafter. Approximately up to 25 subjects may be enrolled in Part C. 
Study Design 
This is a Phase 1/2, open-label, multi-center study of ADXS-503 administered alone and in 
combination with pembrolizumab in subjects with metastatic squamous or non-squamous 
NSCLC. This study will be performed in 2 phases, a safety phase and an efficacy phase, as 
described below. Refer to 
Figure 1 for a schematic of the study design. Simon’s Two-stage design has been incorporated 
for evaluation of subjects in Part B expansion Efficacy phase. 
Safety Phase 
The purpose of the safety phase is to evaluate the safety and tolerability of ADXS-503, 
administered as monotherapy (Part A) and in combination with pembrolizumab (Part B-dose 
escalation), and to determine the MTD or MAD. The preliminary clinical and immunological 
activity of ADXS-503 alone and in combination with pembrolizumab will also be characterized 
in the safety phase. The subject population to be enrolled in Part A and Part B is described 
above. 
In Part A, ADXS-503 will be administered as monotherapy at 2 planned escalating dose levels 
(dose level 1 [1x108 CFU] and dose level 2 [5x108 CFU]). In Part B, ADXS-503 will be 
                               
                         
                             
                           
      
                     
              
          
                     
                         
              
          
            
 
                                        
 
                                                 
         
 
                                                
                          
 
                                   
                                             
                                             
 
                                        
 
                                                            
                                                      
                                                         
                                                               
                                                  
 
                                                             
                                     
                            
                         
                  
                    
              
                      
                       
                  


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Protocol ADXS-503-101 
 
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administered at 2 planned escalating dose levels (dose level 1 [1x108 CFU] and upon Sponsor’s 
decision, may be escalated to dose level 2 [5x108 CFU]) in combination with a fixed dose of 200 
mg of pembrolizumab, as described above. Dose escalation in Part A and Part B will proceed 
according to a 3+3 dose escalation design.  
If treatment with ADXS-503 monotherapy is safe and tolerable at dose level 1 in Part A (based 
on DLT criteria), escalation to dose level 2 in Part A will proceed in parallel with accrual at dose 
level 1 in Part B-dose escalation. If treatment with ADXS-503 + pembrolizumab is safe and 
tolerable at dose level 1 in Part B (based on DLT criteria), this dose can be considered the 
recommended dose for use in Part B-expansion and Part C. In parallel, escalation to dose level 2 
in Part B will proceed (upon Sponsor’s decision) in parallel with accrual in Part C.  
Prior to declaring the MTD in Part A or Part B, dose level(s) previously established to be safe 
may be expanded or intermediate dose levels may be investigated. If a MTD is not established, a 
higher dose level may be evaluated with agreement between the Investigators and the Sponsor 
or study will continue with the recommended dose from Part B-escalation that is demonstrated 
to be safe and well tolerated. Dose escalation rules (cohort size, DLT evaluation interval, etc.) 
will apply to the expanded or additional cohorts. 
Upon completion of dose escalation in Part A, ADXS-503 monotherapy may be evaluated in an 
expansion cohort. This Part A expansion cohort may commence enrollment following 
consultation and agreement between study Investigators and the Sponsor. The expansion cohort 
may be restricted to the tumor type(s) found to be responsive to ADXS-503 monotherapy. The 
dose of ADXS-503 selected for the monotherapy expansion will not exceed the MTD 
established in Part A. However, the dose may be intermediate to those tested in Part A if 
recommended by the Investigators and the Sponsor. Up to approximately 25 subjects will be 
enrolled in this expansion cohort. 
Efficacy Phase 
Upon confirming treatment with ADXS-503 + pembrolizumab is safe and tolerable at dose level 
1 in Part B-escalation (based on DLT criteria), accrual will be initiated in Part B expansion and 
Part C. Hence, the planned dose in Part B-expansion and in Part C will be ADXS-503 1x108 
CFU in combination with 200 mg of pembrolizumab.  
Part B-dose expansion will evaluate preliminary efficacy using a Simon’s Two-stage study 
design in subjects who have failed prior systemic treatment with 1) pembrolizumab 
monotherapy as last therapy or 2) while receiving combination therapy with pembrolizumab and 
platinum based-chemotherapy as last treatment or 3) while receiving pembrolizumab + 
pemetrexed maintenance therapy as last treatment in the metastatic setting. Part B dose-
expansion may enroll up to 43 subjects in the Simon’s Two-stage design (ie, S1 [n=18], and S2 
[n=25]) and up to a total of 140 thereafter.  
The purpose of Part C is to evaluate the safety and preliminary clinical efficacy of ADXS-503 in 
combination with pembrolizumab in subjects who have received no prior systemic treatment in 
the metastatic setting, and whose tumors express PD-L1 [TPS (Tumor Proportion Score) ≥1%] 
as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. 
Toxicities will be evaluated on an ongoing basis in Part B-dose expansion and Part C. If the 
aggregate rate of treatment-related toxicities that meet the DLT criteria exceeds 33% at any time 
(across all subjects in Part B dose-expansion and Part C), the findings will be discussed between 
the Sponsor and study Investigators, and further enrollment may be interrupted. Depending on 
the nature and grade of the toxicities and after assessing the risk/ benefit, treatment may be 
adjusted to a lower dose of ADXS-503 or an alternative treatment schedule. In all cases, the 
dose of pembrolizumab will be fixed at 200 mg. 
Overall treatment and enrollment stopping rules for this study are described in Section 8.1.2. 


CONFIDENTIAL 
 
 
Protocol ADXS-503-101 
 
13 
 
Summary of study 
assessments/ procedures 
• 
In Part B, subject must consent to allow the acquisition of fresh or archival FFPE tumor 
tissue, either a block or unstained slides along with matching blood at baseline, for 
performance of sequencing analysis. 
• 
At least 30 minutes prior to each ADXS-503 infusion, all subjects will receive a pre-
infusion prophylactic regimen of adequate hydration, NSAIDs, antihistamines and 
antiemetics to mitigate the potential for “flu-like” symptoms during or after treatment 
infusion. Vital signs will be monitored every 30 minutes (±5 minutes) starting immediately 
prior to each ADXS-503 infusion, until 4 hours after the end of each ADXS-503 infusion. 
To ensure the clearance of Lm, subjects will receive a 7-day course of oral antibiotics 
starting approximately 48 hours after each ADXS-503 infusion. After the final dose of 
ADXS-503, a 3-week course of oral antibiotics will be administered to ensure the clearance 
of Lm, which will be confirmed by a blood culture.  
• 
Safety will be assessed throughout this study by AE monitoring, physical examination 
findings, vital sign measurements, monitoring of performance status, and clinical laboratory 
values. Adverse events will be graded in severity according CTCAE v4.03. 
• 
Tumor imaging will be performed by contrast-enhanced CT/MRI as follows: 
o 
Part A (ADXS-503 monotherapy): Screening (baseline), at Week 8 (±3 days), at 
Week 16 (± 7 days), followed by every 9 weeks (±7 days) thereafter, until 
confirmed disease progression or treatment discontinuation, whichever occurs 
later.  
o 
Part B dose-escalation and Part B dose-expansion (ADXS-503 + pembrolizumab): 
Screening (baseline) [which corresponds to the most recent tumor assessment that 
is consistent with PD (according to RECIST v1.1) while on treatment with 
pembrolizumab monotherapy, or while receiving combination therapy with 
pembrolizumab + platinum-based chemotherapy or while receiving 
pembrolizumab + pemetrexed maintenance therapy in the metastatic setting as the 
last systemic therapy] . Subsequent scans will be performed at Week 8 (±7 days), 
at Week 16 (± 7 days), followed by every 9 weeks (±7 days) thereafter, until 
confirmed disease progression or treatment discontinuation, whichever occurs 
later. As described above, the first dose of ADXS-503 added to pembrolizumab 
will be administered within 12 weeks of the initial assessment of PD. 
o 
Part C (ADXS-503 + pembrolizumab): Screening (baseline), at Week 8 (±7 days), 
at Week 16 (± 7 days), followed by every 9 weeks (±7 days), until confirmed 
disease progression or treatment discontinuation, whichever occurs later. 
• 
Tumor response will be evaluated by the Investigator (or designee) according to RECIST 
v1.1 as the basis for the primary analysis of tumor response-based endpoints. Exploratory 
analysis of tumor-response will be performed by the Sponsor (or designee) according to 
iRECIST. 
o 
In Part A and Part C, subjects may receive study treatment beyond initial 
Investigator-assessed, RECIST v1.1-defined disease progression, provided the 
subject is stable and is considered by the Investigator to be deriving clinical 
benefit. In Part B-dose-escalation and dose-expansion, all subjects will begin study 
treatment within 12 weeks of initial Investigator-assessed, RECIST v1.1-defined 
disease progression on treatment with last systemic therapy in metastatic setting 
(ie, pembrolizumab alone, or combination therapy with pembrolizumab + 
platinum-based chemotherapy, or pembrolizumab + pemetrexed as maintenance 
therapy) (if eligibility criteria are met). 
o 
In Parts A, B, and C, any apparent CR or PR must be confirmed ≥4 weeks after 
radiological imaging indicating CR or PR. 


CONFIDENTIAL 
 
 
Protocol ADXS-503-101 
 
14 
 
o 
Subjects who achieve a confirmed CR may receive up to 2 additional doses of 
study treatment after the date of confirmed CR but must subsequently discontinue 
treatment. 
o 
The following subjects may be eligible for re-treatment upon disease progression, 
with agreement between the Sponsor and Investigator: 
▪ 
Subjects who achieve a confirmed CR during initial study treatment (Parts 
A, B, and C). 
▪ 
Subjects in Part B and Part C who stop trial therapy after 2 years of 
treatment for reasons other than disease progression or intolerability. 
Note: Tumor response data collected during the re-retreatment period will 
not be used for the primary analysis of tumor response endpoints.  
• 
In Parts A, B and C, evaluable tumor biopsy tissue (fresh or archival) with matched 
peripheral blood samples must be collected at baseline. to evaluate biomarkers and 
correlates of immune response.  Additional blood samples for correlative work will be 
collected during the treatment phase.  
• 
Following treatment discontinuation, all subjects will enter a 1-year survival/treatment and 
Lm surveillance (LmS) follow-up period. Survival status will be confirmed remotely with 
the subject, their physician, or their legally authorized representative every 3 months (±2 
weeks) for 1 year. In addition, during the LmS Follow-up Period, subjects will be contacted 
remotely every 3 months (±2 week) for 1 year to determine whether they have experienced 
for several days, the following symptoms that could potentially be associated with delayed 
listeremia: fever or chills, headache, nausea, confusion, or changes in alertness (for over 72 
hours). As part of the End of Therapy procedures, upon completing the LmS Follow-up 
Period, site staff should instruct subjects to contact the site if they experience any of these 
symptoms, as applicable. 
 
 


CONFIDENTIAL 
 
 
Protocol ADXS-503-101 
 
15 
 
 
 
Figure 1. Study Design 
a. 
Escalation to DL2 in Part A will occur in parallel with accrual at DL1 in Part B 
b. 
Upon completion of DL1 in Part B, Dose-expansion of DL1 in Part B will occur in parallel with accrual in Part C. (Accrual in Part B Dose Level 2 may occur upon Sponsor’s decision). Upon 
Investigators’ assessment and decision, treatment schedule with 1x108 CFU of ADXS-503 + 200 mg of pembrolizumab, IV, could shift from every 3 weeks to every 6 weeks after the first year 
of study therapy. 
      
           
             
                               
                         
                             
                           
      
                     
              
          
                     
                         
              
          
            
            
 
                                        
 
                                                 
         
 
                                                
                          
 
                                   
                                             
                                             
 
                                        
 
                                                               
                                                      
                                                                  
                                                                    
                                                  
 
                                                                   
                                     
 
                         
               
 
              
 
                           
                           
                   
             
                            
                         
                            
                         
                     
                         
              
                            
                         
                      


CONFIDENTIAL 
 
 
Protocol ADXS-503-101 
 
16 
 
c. 
If treatment is not safe/tolerable at DL1 in Part A or Part B dose-escalation, a lower dose level (DL -1; 0.5x108 CFU of ADXS-503) will be evaluated before proceeding with Part B and Part C, 
respectively. 
d. 
Upon completion of dose escalation in Part A, ADXS-503 monotherapy may be evaluated in an expansion cohort. 
Abbreviations: DL: dose level. 
 
 


CONFIDENTIAL 
 
 
Protocol ADXS-503-101 
 
17 
2. 
Schedule of Activities (SoA) 
2.1. 
Safety Phase Part A: ADXS-503 Monotherapy 
Procedure 
 
 
 
Screening1 
First 12 weeks of treatment 2 
Week 13 
to EOT 3 
End of 
Therapy 
(EOT)4 
 
 
Safety 
Follow-
Up21 
 
 
1-year  
Survival/ 
Treatment 
& LmS 
Follow-up 
Period22 
Days 
-30 to -1 
Wk  
1 
Wk 
2 
Wk 
3 
Wk  
4 
Wk 
5 
Wk 
6 
Wk  
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 13  
to EOT 
Administrative Procedures 
Informed consent 5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility review 6 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Issue subject ID card 7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgical history 9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior cancer history 10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant medications 11 
X 
<-------------------------------------------------------------------------------------------------------> 
X 
X 
X 22 
Non-drug treatment/Procedures 12 
X 
<--------------------------------------------------------------------------------------------------------> 
X 
X 
 
Clinical Procedures 
Review adverse events 13 
X 
<--------------------------------------------------------------------------------------------------------> 
X 
X 
 
Physical examination 14 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
ECOG performance status 15 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
Vital signs 16 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
Tumor imaging/ assessments 17 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
 
Pre-infusion prophylaxis 18 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Administer ADXS-503 19 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Administer/dispense prophylactic 
antibiotics 20 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
Safety follow-up phone call/ visit 21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Survival/LmS remote monitoring 22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory Procedures 
Virology 23 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation profile 24 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Blood Count (CBC) with 
differential 25 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
Serum chemistry panel 25 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
Urinalysis 25 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
Pregnancy test 26 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 


CONFIDENTIAL 
 
 
Protocol ADXS-503-101 
 
18 
Procedure 
 
 
 
Screening1 
First 12 weeks of treatment 2 
Week 13 
to EOT 3 
End of 
Therapy 
(EOT)4 
 
 
Safety 
Follow-
Up21 
 
 
1-year  
Survival/ 
Treatment 
& LmS 
Follow-up 
Period22 
Days 
-30 to -1 
Wk  
1 
Wk 
2 
Wk 
3 
Wk  
4 
Wk 
5 
Wk 
6 
Wk  
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 13  
to EOT 
Tumor biopsy sample 27 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Blood draw for cytokines/ 
chemokines 28 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Blood draw for immune correlative 
studies 29 
X 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
 
 
Blood sample for Lm culture 30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
1 
Screening procedures will be performed within 28 days (±2 days) prior to the first dose of study treatment to determine study eligibility.  
2 
Procedures noted here will be performed during the first 12 weeks of study treatment. 
3 
Procedures noted here will be performed from Week 13 up to the end of therapy (EOT). Refer to Table and indicated footnotes. Subjects will receive study treatment 
until a treatment discontinuation criterion is met (see Section 8.1). 
4 
EOT procedures noted here should be completed preferably within 7 days of when the decision is made for a subject to discontinue study treatment. 
5 
Informed Consent must be obtained prior to conducting Screening or baseline evaluations. Procedures conducted as part of the subject’s routine clinical management 
and obtained before signing the Informed Consent Form, may be utilized for Screening or baseline purposes provided the procedures meet the protocol-specified 
criteria. 
6 
Subject eligibility (Inclusion/ Exclusion Criteria) must be reviewed during Screening and confirmed prior to the start of study treatment on Day 1 of the study. 
7 
Subject ID card will identify subject as a participant in this clinical trial and will be provided to subject after Informed Consent is provided. Subject ID card will contain 
trial site information to be used in case of an emergency and will specify that the subject is enrolled in a clinical trial of an experimental agent that may be associated 
with immune-mediated toxicity, induced by Lm.  
8 
Medical history will include all active conditions and any prior conditions that are considered by the Investigator to be clinically significant. Medical history will also 
include an assessment of smoking history. 
9 
Document any non-cancer surgeries, including, but not limited to the placement of artificial (prosthetic) joints, implants and/or devices, such as port/stent implant placed 
prior to study enrollment. 
10 
Document prior cancer history, including prior cancer treatments, surgeries and medications. 
11 
Prior/concomitant medications will be documented from 30 days prior to Screening until 30 days after the final dose of study treatment.  
12 
Document any non-drug treatment and surgical procedures including, but not limited to, artificial (prosthetic) joints, implants and/or devices.  
13 
AEs and SAEs will be assessed starting from the time Informed Consent is obtained through 30 days after the final dose of study treatment or the beginning of any anti-
cancer treatment following the discontinuation of study treatment, whichever comes first. Reporting of ESIs will begin from the date of first dose of study treatment. 
ESIs will be reviewed as they are reported and will be discussed at the time of the dose escalation meetings, and periodically afterwards. All AEs/ECI/SAEs will be 
followed through resolution. All AEs/ESI/SAEs experienced during this period must be recorded on the eCRF. See Section 9.1.5 and Appendix 4. 
14 
A physical examination (PE) must be completed at Screening and within 72 hours prior to the start of each ADXS-503 infusion. Body height will be measured only at 
Screening. Body weight will be measured at all physical examination timepoints. 
15 
ECOG performance status to be evaluated at Screening and within 72 hours prior to the start of each ADXS-503 infusion (see Appendix 11). 
16 
Vital signs will be measured in a semi-supine position after 5 minutes of rest and will include temperature, systolic and diastolic blood pressure, pulse, oxygen 
saturation, and respiratory rate. Vital signs to be measured at Screening. Vital signs will also be measured every 30 minutes (± 5 minutes) starting immediately prior to 
each ADXS-503 infusion, until 4 hours after the end of each ADXS-503 infusion. Subsequent vital sign monitoring will be performed per institutional standard of care. 
17 
Tumor response will be evaluated by the Investigator (or designee) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Tumor imaging in Part 
A will be performed with CT/MRI during Screening (baseline), at Week 8 (±7 days), at Week 16 (±7 days), followed by every 9 weeks (±7 days) thereafter, until 
confirmed disease progression or treatment discontinuation, whichever occurs later. Tumor imaging will occur at this schedule, independent of any adjustments to 


CONFIDENTIAL 
 
 
Protocol ADXS-503-101 
 
19 
Procedure 
 
 
 
Screening1 
First 12 weeks of treatment 2 
Week 13 
to EOT 3 
End of 
Therapy 
(EOT)4 
 
 
Safety 
Follow-
Up21 
 
 
1-year  
Survival/ 
Treatment 
& LmS 
Follow-up 
Period22 
Days 
-30 to -1 
Wk  
1 
Wk 
2 
Wk 
3 
Wk  
4 
Wk 
5 
Wk 
6 
Wk  
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 13  
to EOT 
the treatment schedule. Note: The tumor scan at Week 8 must be performed before the scheduled tumor biopsy at Week 8 (see footnote # 27). See Section 9.4.1 and 
Appendix 10. 
18 
The pre-infusion prophylactic regimen of adequate hydration, NSAIDs, antihistamines and antiemetics will be administered prior to and will be completed at least 30 
minutes before the start of each ADXS-503 infusion. 
19 
Administer ADXS-503 as a single IV infusion over 60 (±10) minutes, every 3 weeks until a treatment discontinuation criterion is met. See Section 7.1 for treatment 
administration instructions. Treatment with ADXS-503 must occur within 3 days of the scheduled infusion day (every 3 weeks ±2 days) unless a delay in dosing is 
required to allow for the resolution of AEs as outlined in Section 7.6. The interval between each ADXS-503 dose should not be less than 2 weeks without Sponsor 
approval. 
20 
All subjects will receive a 7-day course of oral antibiotics after each ADXS-503 infusion to ensure clearance of Lm. The first dose of antibiotics will be administered 
approximately 72 hours after the ADXS-503 infusion. After the final dose of ADXS-503, a 3-week course of oral antibiotics will be administered to ensure the clearance 
of Lm (the first dose administered approximately 48 hours after the final ADXS-503 infusion). See Section 9.2.1.3 for the antibiotic regimen. 
21 
Safety follow-up phone call/ visit to be made 30 days (±5 days) after final dose of study treatment to confirm resolution of any new or ongoing AEs, ESI or SAEs. 
22 
Following treatment discontinuation, all subjects will enter a 1-year survival/treatment and Lm surveillance Follow-up Period. 
• 
Survival status will be confirmed remotely with the subject, their physician, or their legally authorized representative every 3 months (±2 weeks) for up to 1 
year. 
• 
Any subsequent anti-cancer treatment received by the subject during this 1-year period will be recorded. 
• 
During the Lm surveillance Follow-up Period, subjects will be contacted remotely every 3 months (±2 week) to determine whether they have experienced 
for several days, the following symptoms that could potentially be associated with delayed listeremia: fever or chills, headache, nausea, confusion or 
changes in alertness (for over 72 hours). As part of EOT procedures, upon completing the Lm Surveillance period, site staff should instruct subjects to 
contact the site if they experience any of these symptoms, as applicable. 
23 
HBsAg and HCV screening is required for subjects with a history of active hepatitis B or hepatitis C infection. 
24 
PT/INR and aPTT must be measured during Screening. Subsequent testing is to be performed only as clinically indicated. 
25 
All laboratory procedures are to be completed and assessed by the Investigator at Screening and within 72 hours prior to the start of each ADXS-503 infusion, to 
confirm that safety criteria for study treatment are met. If the Screening samples are obtained within 72 hours of the first dose of ADXS-503, only one set of samples 
will be required for both timepoints. See Appendix 2. 
26 
A pregnancy test must be performed at Screening and within 72 hours prior to the start of each ADXS-503 infusion for women of childbearing potential. If the urine test 
is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
27 
During Screening, a fresh tumor biopsy must be obtained if clinically feasible, in the opinion of the Investigator for biomarker analysis. If a fresh biopsy cannot be 
obtained during Screening, the most recently acquired archived tumor biopsy sample may be used for analysis (date of biopsy within 3 years of Screening). For archived 
tumor biopsy samples, sufficient tumor samples should be acquired to allow biomarker testing (eg, at least 12-15 unstained slides). Tumors biopsied at screening will be 
designated as pretreatment biopsies. The baseline biopsy must be from a location that has not been radiated. In addition, a fresh on-treatment biopsy must be obtained 
from a suitable lesion, preferably from a non-target lesion, at Week 8 (± 7 days) or, if not possible, 1 week (±3 days) after next ADXS-503 infusion (Week 11). This on-
treatment biopsy sample must be obtained after the scheduled tumor scan at Week 8 (see Section 9.4.1 and Section 9.5). Note: tumor biopsy samples may not be 
collected after the first 3 subjects in the dose escalation phase with evaluable samples at each dose level are biopsied, or during expansion cohorts. An EOT biopsy will 
be done only if the subject is discontinued before Week 7 (3rd dose) Additional matched biopsy tissue and blood samples at baseline and post treatment or End of 
treatment samples may be collected by sponsor when the Part A expansion cohort is opened.  
28 
Blood samples for cytokine/chemokine analysis will be collected for the first 4 ADXS-503 infusions (Weeks 1, 4, 7, and 10) as follows: 
• 
Within 30 minutes prior to the start of each ADXS-503 infusion and 2 hours after the end of each ADXS-503 infusion (± 15 minutes). 


CONFIDENTIAL 
 
 
Protocol ADXS-503-101 
 
20 
Procedure 
 
 
 
Screening1 
First 12 weeks of treatment 2 
Week 13 
to EOT 3 
End of 
Therapy 
(EOT)4 
 
 
Safety 
Follow-
Up21 
 
 
1-year  
Survival/ 
Treatment 
& LmS 
Follow-up 
Period22 
Days 
-30 to -1 
Wk  
1 
Wk 
2 
Wk 
3 
Wk  
4 
Wk 
5 
Wk 
6 
Wk  
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 13  
to EOT 
29 
Blood samples for immune correlative studies (eg, RNAseq, cfDNA, flow cytometry, and ELISpot analysis) will be collected during Screening, Week 1 (ie, right before 
the first infusion) and 7 days (± 2 days) after the end of each of the first 3 ADXS-503 infusions (Weeks 2, 5, and 8). To monitor the durability of T cell responses, 
subsequent blood samples for PBMCs will be taken at Week 25 (±1 week) and/or at EOT.  
30 
7 days (±3 days) after the completion of the 3-week course of oral antibiotics following the final dose of ADXS-503, a blood sample will be collected to culture for Lm. 
If this blood test cultures positive for Lm, the subject should receive treatment as outlined in Section 9.2.1.3. 


CONFIDENTIAL 
 
 
Protocol ADXS-503-101 
 
21 
2.2. 
Part B (Safety & Efficacy Phases) and Part C: ADXS-503 + Pembrolizumab 
Procedure 
 
 
 
 
Screening1 
First 12 weeks of treatment 2 
Week 
13 to 
EOT 3 
 
End of 
Therapy 
(EOT)4 
 
 
Safety 
Follow-
Up23 
 
 
 
 
1-year 
Survival/ 
Treatment 
& LmS 
Follow-up 
Period 24 
Days 
-42 to -1 
Wk  
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk  
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
 
Wk 13  
to EOT 
 
 
Wk 25 
 
Administrative Procedures 
Informed consent 5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility review 6 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Issue subject ID card 7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgical history 9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior cancer history 10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant medications 
11 
X 
<--------------------------------------------------------------------------------------------------------> 
 
X 
X 
X 24 
Non-drug treatment/Procedures 
12 
X 
<--------------------------------------------------------------------------------------------------------> 
 
X 
X 
 
 
Clinical Procedures 
Review adverse events 13 
X 
<--------------------------------------------------------------------------------------------------------> 
 
X 
X 
 
Physical examination 14 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
ECOG performance status 15 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
Vital signs 16 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
Tumor imaging/ assessments 17 
X 
 
 
 
 
 
 
 
X17 
 
 
 
 
X 
 
X 
 
 
Administer Pembrolizumab 18,19 
 
X18 
 
 X18 
 
 
X18 
 
 
X18 
 
 
X18 
 
 
 
 
ADXS-503 Pre-infusion 
prophylaxis 20 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Administer ADXS-503 21 
 
X18 
 
 X18 
 
 
X18 
 
 
X18 
 
 
X18 
 
 
 
 
Administer/dispense 
prophylactic antibiotics 22 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
Safety follow-up phone call/ 
visit 23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Survival/follow up and LmS 
remote monitoring24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Laboratory Procedures 
Virology 25 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation profile 26 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
 
Protocol ADXS-503-101 
 
22 
Procedure 
 
 
 
 
Screening1 
First 12 weeks of treatment 2 
Week 
13 to 
EOT 3 
 
End of 
Therapy 
(EOT)4 
 
 
Safety 
Follow-
Up23 
 
 
 
 
1-year 
Survival/ 
Treatment 
& LmS 
Follow-up 
Period 24 
Days 
-42 to -1 
Wk  
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk  
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
 
Wk 13  
to EOT 
 
 
Wk 25 
Complete Blood Count (CBC) 
with differential 27 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
Serum chemistry panel 27 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
Urinalysis 27 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
T3, FT4, TSH 27, 28 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
Pregnancy test 29 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Tumor biopsy sample 30, 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD-L1 expression and EGFR 
and ALK mutation testing 31 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood draw for immune 
correlative studies 32 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Blood sample for Lm culture 33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
1 
In Part B, screening procedures will be performed within 12 weeks of the most recent tumor assessment showing PD while on treatment with pembrolizumab 
monotherapy, to determine study eligibility. Subjects must receive the first dose of ADXS-503 within 12 weeks of this initial assessment of PD. ADXS-503 will be 
administered as add-on therapy to pembrolizumab for at least 4 weeks. In Part C, screening procedures will be performed within 28 days (±2 days) prior to the first dose 
of study treatment to determine study eligibility. 
2 
Procedures noted here will be performed during the first 12 weeks of study treatment for Part B andfor Part C. 
3 
Procedures noted here will be performed from Week 13 (Part Band Part C) up to the end of therapy (EOT). Refer to Table and indicated footnotes. Subjects will receive 
study treatment for up to 2 years or until a treatment discontinuation criterion is met (see Section 8.1). 
4 
EOT procedures noted here should be completed preferably within 7 days of when the decision is made for a subject to discontinue study treatment. 
5 
Informed Consent must be obtained prior to conducting Screening or baseline evaluations. Procedures conducted as part of the subject’s routine clinical management 
and obtained before signing the Informed Consent Form, may be utilized for Screening or baseline purposes provided the procedures meet the protocol-specified criteria. 
6 
Subject eligibility (Inclusion/ Exclusion Criteria) must be reviewed during Screening and confirmed prior to the start of study treatment on Day 1 of the study. 
7 
Subject ID card will identify subject as a participant in this clinical trial and will be provided to subject after Informed Consent is provided. Subject ID card will contain 
trial site information to be used in case of an emergency and will specify that the subject is enrolled in a clinical trial of an experimental agent that may be associated 
with immune-mediated toxicity, induced by Lm. 
8 
Medical history will include all active conditions and any prior conditions that are considered by the Investigator to be clinically significant. Medical history will also 
include an assessment of smoking history. 
9 
Document any non-cancer surgeries, including, but not limited to the placement of artificial (prosthetic) joints, implants and/or devices, such as port/stent implant placed 
prior to study enrollment. 
10 
Document prior cancer history, including prior cancer treatments, surgeries and medications. 
11 
Prior/concomitant medications will be documented from 30 days prior to Screening until 30 days after the final dose of study treatment. 
12 
Document any non-drug treatment and surgical procedures including, but not limited to, artificial (prosthetic) joints, implants and/or devices. 


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Protocol ADXS-503-101 
 
23 
13 
AEs and SAEs will be assessed starting from the time Informed Consent is obtained through 30 days after the final dose of study treatment or the beginning of any anti-
cancer treatment following the discontinuation of study treatment, whichever comes first. Reporting of ESIs will begin from the date of first dose of study treatment. 
ESIs will be reviewed as they are reported and will be discussed at the time of the dose escalation meetings, and periodically afterwards. All AEs/ECI/SAEs will be 
followed through resolution. All AEs/ESI/SAEs experienced during this period must be recorded on the eCRF. See Section 9.1.5 and Appendix4. During the LmS 
Follow-up Period, AEs and SAEs related to listeremia will be assessed. 
14 
A physical examination (PE) must be completed at Screening and within 72 hours prior to the start of study treatment on each treatment day. Body height will be 
measured only at Screening. Body weight will be measured at all physical examination timepoints. 
15 
ECOG performance status to be evaluated at Screening and within 72 hours prior to the start of study treatment on each treatment day (see Appendix 11). 
16 
Vital signs will be measured in a semi-supine position after 5 minutes of rest and will include temperature, systolic and diastolic blood pressure, pulse, oxygen 
saturation, and respiratory rate. Vital signs to be measured at Screening. On treatment days, vital signs will be measured prior to the administration of pembrolizumab 
and subsequently as per institutional standard of care until the administration of ADXS-503. Vital sign monitoring for ADXS-503 will then occur every 30 minutes (± 5 
minutes) starting immediately prior to each ADXS-503 infusion, until 4 hours after the end of each ADXS-503 infusion. Subsequent vital sign monitoring will be 
performed per institutional standard of care. 
17 
Tumor response will be evaluated by the Investigator (or designee) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Tumor imaging in Part 
B will be performed with CT/MRI during Screening (baseline), which corresponds to the most recent tumor assessment that is consistent with PD (according to RECIST 
v1.1) while on treatment with pembrolizumab monotherapy as last therapy, while receiving combination therapy with pembrolizumab + platinum-based chemotherapy 
or while receiving pembrolizumab + pemetrexed as maintenance therapy, as last therapy in the metastatic setting. The first dose of ADXS-503 will be administered 
within 12 weeks of the initial assessment of PD. Subsequent scans will be performed at Week 8 (±7 days), at Week 16 (±7 days), followed by every 9 weeks (±7 days) 
thereafter, until confirmed disease progression or treatment discontinuation, whichever occurs later. Similarly, tumor imaging in Part C will be performed at Screening 
(baseline), at Week 8 (±7 days), at Week 16 (±7 days), followed by  every 9 weeks (±7 days) thereafter, until confirmed disease progression or treatment 
discontinuation, whichever occurs later  Tumor imaging will occur at this schedule, independent of any adjustments to the treatment schedule. Note: See Section 
9.4.1 and Appendix 10. 
18 
On each treatment day, pembrolizumab will be infused first, followed approximately 60 (± 15) minutes after the end of the pembrolizumab infusion by the ADXS-503 
infusion (see footnote # 19 and footnote # 21). Treatment will continue every 3 weeks starting at Week 1 (±2 days) until the completion of 2 years of treatment, or until 
another treatment discontinuation criterion is met (see Section 8.1). 
19 
Administer pembrolizumab as a single IV infusion over 30 (±5) minutes. See Section 7.1 for treatment administration instructions. Treatment with pembrolizumab must 
occur within 3 days of the scheduled infusion (every 3 weeks ±2 days) day unless a delay in dosing is required to allow for the resolution of AEs as outlined in 
Section 7.6. The interval between each pembrolizumab dose should not be less than 2 weeks without Sponsor approval. Treatment will continue every 3 weeks (±2 
days) for approximately the first year from the first dose on this study. Thereafter, the PI may decide to continue dosing at Q3W or change to Q6W schedule until the 
completion of 2 years of treatment on this study (see footnote 21), or until another treatment discontinuation criterion is met (see Section 8.1). 
20 
The pre-infusion prophylactic regimen of adequate hydration, NSAIDs, antihistamines and antiemetics will be administered prior to and will be completed at least 
30 minutes before the start of each ADXS-503 infusion. 
21 
Administer ADXS-503 as a single IV infusion over 60 (±10) minutes, every 3 weeks starting at Week 1 (±2 days) until a treatment discontinuation criterion is met. See 
Section 7.1 for treatment administration instructions. Treatment with ADXS-503 must occur within 3 days of the scheduled infusion day (every 3 weeks ±2 days) unless 
a delay in dosing is required to allow for the resolution of AEs as outlined in Section 7.6. The interval between each ADXS-503 dose should not be less than 2 weeks 
without Sponsor approval. Upon Investigator assessment and discretion, the treatment schedule of ADXS-503 (1x108 CFU) + 200 mg of pembrolizumab, IV, could shift 
from every 3 weeks to every 6 weeks after the first year of study treatment. 
22 
All subjects will receive a 7-day course of oral antibiotics after each ADXS-503 infusion to ensure clearance of Lm. The first dose of antibiotics will be administered 
approximately 48 hours after the ADXS-503 infusion. After the final dose of ADXS-503, a 3-week course of oral antibiotics will be administered to ensure the clearance 
of Lm (the first dose administered approximately 48 hours after the final ADXS-503 infusion). See Section 9.2.1.3 for the antibiotic regimen. 
23 
Safety follow-up phone call/ visit to be made 30 days (±5 days) after final dose of study treatment to confirm resolution of any new or ongoing AEs, ESI or SAEs. 
24 
Following treatment discontinuation, all subjects will enter a 1-year survival/treatment Follow-up Period. 
• 
Survival status will be confirmed remotely with the subject, their physician, or their legally authorized representative every 3 months (±2 weeks) for up to 1 
year. 
• 
Any subsequent anti-cancer treatment received by the subject during this 1-year period will be recorded. 


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24 
• 
During the Lm surveillance Follow-up Period, subjects will also be contacted remotely every 3 months (±2 week) for 1 year to determine whether they have 
experienced for several days, the following symptoms that could potentially be associated with delayed listeremia: fever or chills, headache, nausea, 
confusion or changes in alertness (for over 72 hours). As part of EOT procedures, upon completing the Lm Surveillance period, site staff should instruct 
subjects to contact the site if they experience any of these symptoms, as applicable. See Section 9.2.1.4. 
25 
HBsAg and HCV screening is required for subjects with a history of active hepatitis B or hepatitis C infection. 
26 
PT/INR and aPTT must be measured during Screening only if clinically indicated. 
27 
All laboratory procedures are to be completed and assessed by the Investigator at Screening and within 72 hours prior to the start of study treatment on each treatment 
day, to confirm that safety criteria for study treatment are met. If the Screening samples are obtained within 72 hours of the first dose of treatment on Day 1, only one set 
of samples will be required for both timepoints. See Appendix 2. 
28 
Thyroid function tests to be performed at the local laboratory. Samples will be collected at Screening, followed by every 2 doses of pembrolizumab. 
29 
A pregnancy test must be performed at Screening and within 72 hours prior to the start of study treatment on each treatment day for women of childbearing potential. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: a pregnancy test will not be required prior to the first dose of 
pembrolizumab at Week 2 (it will be required prior to the first ADXS-503 dose at Week 1). 
30 
During Screening for subjects in Part B and Part C tumor tissue collection with matched blood at screening is mandatory for all patients in the study. A fresh tumor 
biopsy must be obtained if clinically feasible, in the opinion of the Investigator for biomarker analysis. If a fresh biopsy cannot be obtained during Screening, the most 
recently acquired archived tumor biopsy sample may be used for analysis (date of biopsy within 3 years of Screening). The baseline biopsy must be from a location that 
has not been radiated. (see Section 9.4.1 and Section 9.5). Sufficient tumor samples should be acquired to allow biomarker testing (eg, at least 12-15 unstained slides). 
Tumor tissue and matching blood samples collected during Screening will be used for sequencing analysis.  
31 
Clinical site must provide documentation of tumor PD-L1 expression and EGFR mutation and/or ALK translocation status as evaluated by FDA-approved tests in all 
patients from Part B and Part C. If the site is unable to provide this source documentation, PD-L1 expression and/or EGFR/ALK testing should be performed per 
institutional standard of care (see Section 9.5). Only subjects whose tumors express PD-L1 [Tumor Proportion Score (TPS)] ≥1% as determined by an FDA-approved 
test will be eligible for enrollment in Part C (see Section 9.4.1 and Section 9.5). 
32 
Blood samples for exploratory immune correlative studies (eg, RNAseq, cfDNA, flow cytometry and ELISPOT analysis) may be collected in up to 25 total patients 
from Part B and Part C during Screening, at Week 1 (ie, right before the first infusion), and 7 days (±2 days) after the end of each of the first 3 ADXS-503 infusions 
(Weeks 2, 5, and 8) and EOT. Samples for cfDNA are only collected  at week 1 if samples are not collected during screening. To monitor the durability of T cell 
responses, subsequent blood samples for PBMCs may be taken at Week 25 (±1 week) and/or at end of treatment.  
33 
7 days (±3 days) after the completion of the 3-week course of oral antibiotics following the final dose of ADXS-503, a blood sample will be collected to culture for Lm. 
If this blood test cultures positive for Lm, the subject should receive treatment as outlined in Section 9.2.1.3.   
1 
.


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25 
3. 
Introduction 
3.1. 
Background on Non-Small Cell Lung Cancer 
Lung cancer is the leading cause of cancer death in the United States, with 154,000 deaths 
estimated in 2018. Lung cancer is also the second-leading cancer diagnosed in the United States 
with 234,000 new cases estimated in 2018. Globally, lung cancer is both the leading cause of 
cancer diagnoses (1.8 million) and cancer deaths (1.6 million) annually (American Cancer Society, 
2019; Ferlay, 2015). 
Lung cancers can be broadly divided into two histological groups: non-small cell lung cancer 
(NSCLC) and small cell lung cancer (SCLC). Non-small cell lung cancer accounts for 
approximately 84% of lung cancers and can be subclassified according to squamous and non-
squamous (including adenocarcinoma and large cell carcinoma) histological types (Luo, 2013). 
Patients diagnosed with early-stage NSCLC may be cured with surgery and/or radiotherapy. 
However, more than 50% of patients are diagnosed with advanced or metastatic disease, for which 
systemic treatment is the standard of care (Ferlay, 2015; Luo 2013). 
 
Traditionally, cytotoxic chemotherapy has been the mainstay of front-line treatment for patients 
with metastatic NSCLC.  Multiple randomized clinical trials established platinum-based doublets 
as the most active regimens, because of a demonstrated improvement in overall survival (OS), 
when compared with best supportive care (Schiller, 2002). However, chemotherapy yields only a 
modest clinical benefit and is limited by toxicity and the development of resistance. Only 15-32% 
of patients treated with platinum-based chemotherapy achieve an objective tumor response, and 
most patients experience disease progression within 3-6 months (Kelly, 2001; Scagliotti, 2002; 
Scagliotti, 2008; Schiller 2002). 
Over the past decade and a half, progress in characterizing the molecular biology of NSCLC, has 
provided the opportunity for a targeted therapeutic approach that has advanced the treatment 
landscape at a rapid pace (Luo 2013). Three key therapeutic milestones were the approval in 2003 
and 2004 of the tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, and the approval in 2006 
of the angiogenesis inhibitor, bevacizumab, in combination with platinum-based chemotherapy 
(Nguyen-Ngoc, 2017; Sandler, 2006; Shepherd, 2005; Stinchcombe, 2007). Multiple TKIs were 
developed over the next decade for the limited subset of patients with activating mutations in the 
epidermal growth factor receptor (EGFR) and other mutated proteins that play key roles in cell 
growth and survival. TKIs are now an established option for front-line management of patients 
with NSCLC that harbor these mutations (Nguyen-Ngoc 2017; Zappa, 2016). 


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The next advancement was the development of immune checkpoint inhibitors, which took 
advantage of pre-existing immune responses to NSCLC, and provided a new treatment option for 
patients who were not candidates for TKI treatment. Multiple immune checkpoint inhibitors have 
now been approved for the front-line and later management of NSCLC, firmly establishing 
immunotherapy as a valid treatment strategy for this malignancy (Malhotra, 2017; Nguyen-Ngoc 
2017; Zappa 2016). 
A variety of treatment options are available for patients with NSCLC, based on factors that include 
histology (squamous or non-squamous), the presence of specific biomarkers, and the ability to 
tolerate treatment with regimens that incorporate bevacizumab (Malhotra 2017; Zappa 2016). 
However, despite considerable progress, outcomes remain poor for patients with advanced 
NSCLC. The estimated 5-year survival for all stages of NSCLC combined is approximately 18%, 
and for patients with metastatic disease, the 5-year survival estimate is less than 5% (American 
Cancer Society, 2019; Ferlay, 2015). 
3.1.1. Mutational Burden in Non-Small Cell Lung Cancer 
Genomic sequencing reveals that NSCLC, like other forms of cancer, develops as a consequence 
of accumulated mutations.  These mutations trigger malignant transformation that results in cancer 
over the course of 2 to 3 decades (Massion, 2003). The concept of mutational burden has been 
introduced as a way to capture the number of mutations in the genome of a tumor (Alexandrov, 
2013). Most mutations in NSCLC are somatically acquired as errors in DNA replication or as DNA 
damage caused by carcinogens such as tobacco smoke (Liu, 2012). 
Some mutations, termed driver mutations, play a key role in oncogenesis and malignant 
progression.  Up to 60% of lung adenocarcinomas and up to 80% of lung squamous cell carcinomas 
harbor at least one known driver mutation. The remaining tumor mutational burden consists of 
passenger mutations, which develop as a consequence of the genetic instability that develops in 
parallel with malignant progression (Alamgeer, 2013; Chan, 2015; Nguyen-Ngoc 2017; Savas, 
2013). 
Mutations in driver oncogenes or tumor suppressor genes encode for proteins (typically receptor 
or nonreceptor tyrosine kinases) with altered activity (gain-of-function/ loss-of-function) that 
stimulate a complex cascade of signaling pathways, such as RAS-RAF-MEK-ERK, PI3K-AKT-
mTOR or JAK-STAT, ultimately leading to uncontrolled cell proliferation, evasion of apoptosis, 
and other oncogenic alterations (Chan 2015). 
A notable aspect of mutational burden for most cancers, including NSCLC, is that several 
mutations occur in a limited set of genes, known as mutation hotspots. Hotspot mutations in 
NSCLC consist of certain driver mutations that appear with high frequency amongst patients with 
NSCLC and represent common or shared somatic mutations (Chang, 2016). For example, driver 


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27 
mutations in KRAS, EGFR and BRAF genes are common in non-squamous NSCLC, and additional 
oncogenes have recently been documented (eg, ERBB2, MET, HRAS and NRAS: Figure 2A) 
(TCGA, 2014). In squamous cell NSCLC, driver mutations in TP53, CDKN2A, PIK3CA, PTEN, 
MLL2 and NOTCH genes are common (Figure 2B) (TCGA, 2012). 
 
                    
            
                   
 
Figure 2. Driver mutations in non-small cell lung cancer. 
(A) New candidate driver oncogenes (blue: 13% cases) and known somatically activated driver events (red: 63%) that 
activate the (RTK)/RAS/RAF pathway in 230 lung adenocarcinomas (TCGA, 2014); (B) Significant mutated genes 
in squamous cell NSCLC (TCGA, 2012). 
In addition to accumulating mutations, tumor cells may abnormally express or overexpress non-
mutated genes. Examples of these types of tumor-associated antigens (TAAs) are proteins 
normally expressed only during embryonic development (oncofetal antigens; OFAs) or cancer 
testis antigens (CTAs), which are proteins whose normal expression is restricted to male germ 
cells in the immune-privileged testis. Aberrant expression of OFAs (eg, CEACAM) or CTAs 
(eg, MAGE, NY-ESO-1) occurs in most patients with NSCLC (Reche, 2005). 


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3.2. 
Targeting Driver Mutations in Metastatic Non-Small Cell Lung 
Cancer 
To date, several TKIs have been developed to target certain driver mutations found in NSCLC. 
These targeted therapies exert their anti-tumor activity by disrupting the molecular signaling 
pathways of specific mutated proteins, resulting in cancer cell death (Chan 2015; Hirsh, 2018; 
National Comprehensive Cancer Network (NCCN), 2018; Zappa 2016). 
Unfortunately, currently approved TKIs are limited to the subset of patients (~20-25%) that harbor 
aberrations in EGFR, ALK, ROS1 and BRAF genes. Other known driver mutations remain 
unactionable, most notably in squamous cell carcinoma (Chan 2015; NCCN, 2018). 
Furthermore, despite objective response rates of up to approximately 80%, the long-term 
effectiveness of TKI treatment is limited by the inevitable development of acquired resistance, or 
the presence of resistant subsets of cancer cells from the time of treatment initiation. Most patients 
treated with currently approved TKIs ultimately experience disease progression within 10-19 
months (Chan 2015; Hirsh 2018; Soria, 2018; Zappa 2016).  
Therefore, existing targeted approaches with TKI agents are suboptimal, and new treatment 
strategies are needed. 
3.3. 
Immunotherapy in Metastatic Non-Small Cell Lung Cancer 
The recognition that NSCLC tumors harbor a high number of somatic mutations suggests the 
possibility of utilizing the power of the immune system to attack cancer cells by identifying tumor-
specific mutated proteins as antigens. An important advantage of this strategy over TKI therapy, 
is that the immune system can target mutated proteins regardless of their role in driving 
malignancy. This means that the mutations that limit the duration of sensitivity to TKIs, will not 
limit the immune system. Furthermore, the immune system can elicit anti-tumor immunity by 
recognizing mutated proteins that are currently unactionable with available TKI options 
(eg, KRAS, TP53, and others). 
In addition, the immune system can target TAAs (such as OFAs and CTAs), that are aberrantly 
expressed in NSCLC tumors, further extending the therapeutic potential of immunotherapy 
strategies. 
Cancer immunotherapy rests on the premise that malignant cells can be recognized as foreign 
rather than as self and, as such, can be attacked by the immune system. An effective immune 
response in this setting relies on immune surveillance, where antigens expressed on cancer cells 
(such as somatic mutation-derived antigens or TAAs) are recognized by the immune system, 
resulting in an anti-tumor immune response and, ultimately, cancer cell death (Chen, 2013; Dunn, 
2002; Zitvogel, 2006). However, tumor cells can employ multiple mechanisms to evade immune 


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29 
detection.  Programmed cell death protein 1 (PD-1) is a cell surface receptor expressed on activated 
T cells, and when bound to its ligand (PD-L1 or PD-L2) on tumor cells, functions as a checkpoint 
to halt or limit the anti-cancer T cell response. Aberrant expression of PD-L1 or PD-L2 has been 
observed in multiple tumor types; clear evidence of how tumors can exploit and co-opt this 
pathway to avoid immune-mediated eradication of cancerous cells (Carter, 2002; Freeman, 2000; 
Keir, 2008; Latchman, 2001). Alternatively, tumors may evade immune detection via tumor-
mediated recruitment of immunosuppressive cells (including regulatory T cells [Tregs] and 
myeloid-derived suppressor cells [MDSCs]), which suppress the function of effector T cells (Chen 
2013). 
One approach to assist the immune system in overcoming these tactics is through the use of 
immune checkpoint inhibitors. Immune checkpoint inhibitors are a type of immunotherapy that 
release the brakes on the immune system, thereby improving the ability of tumor-specific T cells 
to function (Pardoll, 2012). The first immune checkpoint inhibitor, ipilimumab (targeting cytotoxic 
T-lymphocyte-associated protein 4 [CTLA-4 ]), was approved for advanced melanoma in 2011 
(Hodi, 2010). It is worth noting that melanoma and NSCLC have of the highest mutational burden 
amongst cancers; a consequence of continual exposure to ultraviolet radiation from the sun, in the 
case of melanoma, and in large part to the numerous mutagens in cigarette smoke, in the case of 
NSCLC (Alexandrov 2013). Checkpoint inhibitors have now been successfully developed to treat 
patients with NSCLC. 
To date, the immune checkpoint inhibitors pembrolizumab, nivolumab and atezolizumab have 
been approved to treat both squamous and non-squamous metastatic NSCLC (Borghaei, 2015; 
Brahmer, 2015; Herbst, 2016; Langer, 2016; Reck, 2016; Rittmeyer, 2017). These 
immunotherapies work by interrupting the suppression of pre-existing T cells by blocking the PD-
1:PD-L1/PD-L2 checkpoint axis, which normally halts or limits a T cell response. All three 
checkpoint inhibitors (pembrolizumab, nivolumab and atezolizumab) have demonstrated 
meaningful clinical benefit over docetaxel as monotherapy in the second-line setting and are 
currently approved (Borghaei, 2015; Brahmer, 2015; Herbst, 2016; Rittmeyer, 2017). In the first-
line setting, pembrolizumab has also been approved as monotherapy and in combination with 
chemotherapy (Brahmer, 2017; Langer 2016; Reck 2016). Additional studies are under evaluation 
with pembrolizumab, nivolumab, and atezolizumab in the first-line setting, as described below. 
3.3.1. Immune Checkpoint Inhibitors in First-Line Metastatic Non-
Small Cell Lung Cancer 
Pembrolizumab is approved as monotherapy in the first-line setting, in patients with squamous or 
non-squamous metastatic NSCLC, with high PD-L1 expression (≥50%) and without an EGFR or 
ALK mutation. Pembrolizumab received approval in this setting based on the results from the 
Keynote 024 study, which evaluated pembrolizumab monotherapy compared with platinum-based 


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30 
chemotherapy. Updated data with a median follow-up of 2 years, showed an improvement in OS 
(median of 30 months vs. 14.2 months; hazard ratio [HR]=0.63), progression-free survival (PFS) 
(median of 10.3 vs. 6 months; HR=0.50) and objective response rate (ORR) (45.5% vs. 29.8%) in 
favor of pembrolizumab (Brahmer 2017; Reck 2016). 
Pembrolizumab has also received accelerated approval in the first-line setting in combination with 
pemetrexed and carboplatin chemotherapy, in patients with non-squamous metastatic NSCLC and 
without an EGFR or ALK mutation (irrespective of PD-L1 expression). Accelerated approval in 
this setting was based on the results from the Keynote 021 study. Updated data with a median 
follow-up of 23.9 months, showed a 14.7-month median increase in PFS (median of 24 months vs. 
9.3 months; HR=0.53) and an improvement in ORR (57% vs. 30%) for the combination of 
pembrolizumab with pemetrexed-carboplatin compared with pemetrexed-carboplatin alone. The 
HR for OS was 0.56 in favor of the pembrolizumab combination (OS data are immature) (Gentzler, 
2018; Langer 2016). 
The confirmatory trial (Keynote 189) in subjects with treatment-naïve non-squamous metastatic 
NSCLC and without an EGFR or ALK mutation is ongoing. In this trial, subjects are randomized 
in a 2:1 ratio to receive pemetrexed-platinum chemotherapy in combination with pembrolizumab 
or placebo for 4 cycles, followed by pembrolizumab or placebo for up to 35 cycles with 
pemetrexed maintenance. Preliminary data, with a median follow-up of 10.5 months, showed a 
3.9-month median increase in PFS (8.8 months vs. 4.9 months; HR=0.52), and a 12-month OS rate 
benefit (69.2% vs. 49.4%; HR=0.49) for the combination of pembrolizumab and chemotherapy 
compared with placebo and chemotherapy. The benefit in PFS and 12-month OS rate was observed 
irrespective of PD-L1 expression. The ORR and duration of response for each arm was 47.6% vs. 
18.9% and 11.2 months vs. 7.8 months, respectively (Gandhi, 2018). 
In subjects with metastatic squamous cell NSCLC, pembrolizumab has been evaluated in the first-
line setting in combination with carboplatin-paclitaxel/nab-paclitaxel vs. placebo and carboplatin-
paclitaxel/nab-paclitaxel (Keynote 407). In this trial, subjects are randomized in a 1:1 ratio to 
receive chemotherapy with pembrolizumab or placebo for 4 cycles, followed by pembrolizumab 
or placebo for up to 35 cycles. Preliminary data, with a median follow-up of 7.7 months, showed 
a 4.6-month improvement in median OS (median of 15.9 vs. 11.3 months; HR=0.64) with 
pembrolizumab in combination with chemotherapy compared with placebo and chemotherapy. 
The benefit in OS was observed irrespective of PD-L1 status. Progression-free survival (median 
of 6.4 months vs. 4.8 months; HR=0.56) and ORR (58.4% vs. 35%) also favored the combination 
of pembrolizumab with chemotherapy (Paz-Ares, 2018). Pembrolizumab in combination with 
chemotherapy in this setting, is yet to be approved. 
Progression-free survival and OS have also been evaluated in the first-line setting with nivolumab 
in combination with ipilimumab vs. chemotherapy, in subjects with metastatic squamous or non-


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31 
squamous NSCLC, without EGFR or ALK mutations, and with a high tumor mutational burden 
(≥10 mutations per megabase). In this study (CheckMate 227), the PFS amongst subjects with high 
tumor mutational burden was improved with nivolumab + ipilimumab compared with 
chemotherapy. The 12-month PFS rate was 42.6% with nivolumab + ipilimumab vs. 13.2% with 
chemotherapy, and the median PFS was 7.2 vs. 5.5 months (HR=0.58). The ORR was 45.3% for 
nivolumab + ipilimumab and 26.9% with chemotherapy. The combination of nivolumab + 
ipilimumab in this setting, is yet to be approved (Hellmann, 2018). 
Furthermore, atezolizumab has been evaluated in the first-line setting in combination with 
platinum-based chemotherapy and bevacizumab in subjects with metastatic non-squamous 
NSCLC (IMpower 150). Subjects were enrolled in this trial irrespective of PD-L1 expression, and 
without regard to EGFR or ALK mutation status. Updated data with a median follow-up of 
approximately 15 months, showed a 1.5-month median increase in PFS (median of 8.3 months vs. 
6.8 months; HR=0.617) for the combination of atezolizumab with chemotherapy-bevacizumab 
compared with chemotherapy-bevacizumab alone. The improvement in PFS was observed across 
all PD-L1 subgroups (Socinski, 2018). Additionally, in subjects with metastatic squamous cell 
NSCLC, the combination of atezolizumab with carboplatin-paclitaxel or carboplatin-nab-
paclitaxel vs. carboplatin-nab-paclitaxel is under evaluation in the IMpower 131 trial. Preliminary 
data, with a median follow-up of 17.1 months, showed a median PFS benefit of 0.7 months for 
atezolizumab in combination with carboplatin-nab-paclitaxel vs. carboplatin-nab-paclitaxel (6.3 
months vs. 5.6 months; HR= 0.715). The PFS benefit was observed across all PD-L1 subgroups. 
The ORR was 49% and 41% for each group, respectively (Jotte, 2018). 
3.3.2. The Unmet Need for New Immunotherapies to Treat Patients 
with Metastatic Non-Small Cell Lung Cancer 
While PD-1/ PD-L1 checkpoint inhibitors have improved the treatment paradigm for metastatic 
NSCLC, the data described above shows that only approximately one-half of patients achieve an 
objective tumor response. Moreover, the PFS data in Keynote 189, Keynote 407, IMpower 150, 
IMpower 131 and CheckMate 227 show that approximately 50-60% of patients experience disease 
progression within one year of combination therapy with PD-1/ PD-L1 checkpoint inhibitors, 
regardless of the agents used (eg, VEGF inhibitor, ipilimumab and/or chemotherapy). This 
suggests that in metastatic NSCLC, the efficacy of immune checkpoint inhibitors requires the 
presence of another element of the immune response; a missing element. 
Several insights suggest ways to optimize the anti-cancer activity of immune checkpoint inhibitors. 
The first insight is that pre-existing anti-cancer immunity is a pre-requisite for the activity of 
checkpoint inhibitors (Dammeijer, 2017). Secondly, the mutational burden, and thus number of 
mutation-derived tumor antigens, is an important determinant of the activity of checkpoint 


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32 
inhibitors (Goodman, 2017; Rizvi, 2015). Furthermore, immunosuppressive factors (such as Tregs 
and MDSCs) in the tumor microenvironment (TME) are able to establish or maintain immune 
tolerance despite inhibition of immune checkpoints (Weber, 2018). 
These observations suggest that an immunotherapeutic option that could directly 1) activate innate 
immunity to create an environment that supports anti-cancer immune system activation;  
2) increase the number and breadth of T cells specific for NSCLC-associated tumor antigens and 
3) reduce the immunosuppressive actions of MDSCs and Tregs within the TME, would be a 
promising approach to improve treatment outcomes. 
3.4. 
Overview of ADXS-503 
The first step of effective immunotherapy is to alert the immune system to the presence of cancer 
by delivering tumor-specific antigens to antigen-presenting cells (APCs). Since the immune 
system’s raison d'être is to detect and eliminate infection, an infection or an apparent infection is 
the best method to engage the immune system. 
ADXS-503 is a live attenuated Listeria monocytogenes (Lm)-based immunotherapy entering 
clinical development for the treatment of squamous and non-squamous NSCLC. ADXS-503 is 
bioengineered to secrete an antigen-adjuvant fusion protein consisting of a truncated nonhemolytic 
fragment of listeriolysin O (tLLO) fused to a total of 22 tumor antigens. Of these tumor antigens, 
11 consist of peptides derived from tumor-specific somatic mutations that commonly occur in 
NSCLC patients (‘hotspot mutation peptide antigens’), and 11 consist of sequence-optimized 
peptide antigens derived from commonly occurring tumor-associated antigens (‘sequence-
optimized TAA peptide antigens’), which include OFAs and CTAs. The Lm component of ADXS-
503 serves as a delivery system for these tumor antigens, which are present in intra-bacterial 
plasmid constructs, the other component of ADXS-503. The proposed mechanism of action of 
ADXS-503 is to stimulate both the innate and adaptive immune systems to initiate a coordinated 
anti-tumor response culminating in the de novo generation of tumor antigen-specific T cells that 
are capable of infiltrating and destroying NSCLC tumors that express the targeted antigens. 
ADXS-503 was designed so that 42% of patients with NSCLC will express at least one of the 
targeted hotspot mutation peptide antigens and that >90% will express at least one of the TAAs 
targeted by the sequence-optimized TAA peptide antigens. By combining these shared, commonly 
expressed antigen targets into a single Lm-based immunotherapy, ADXS-503 provides the 
potential for a potent, disease-specific approach to treating patients with NSCLC. 
In addition to the generation of antigen-specific T cell responses, treatment with Lm-based 
immunotherapies has been shown to reprogram the TME, by reducing the frequencies and function 
of immunosuppressive Tregs and MDSCs within the TME, and upregulating PD-L1 expression 
(see Section 3.4.2). 


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ADXS-503 was developed to be used alone and in combination with standard of care agents in 
NSCLC, such as immune checkpoint inhibitors. In combination with immune checkpoint 
blockade, ADXS-503 has the potential to optimize immunotherapy, and even produce synergistic 
clinical activity, given complementary mechanisms of immune stimulation and reversal of immune 
tolerance (see Section 3.4.5 for clinical and nonclinical data supporting this approach). 
Based on these properties, ADXS-503 is a promising cancer immunotherapy for treating patients 
with metastatic squamous or non-squamous NSCLC. Please refer to the ADXS-503 Investigator’s 
Brochure (IB) for additional details. 
3.4.1. Description of ADXS-503 Construct 
ADXS-503 consists of LmddA, a highly attenuated strain of Lm bacteria, stably transformed with 
a DNA plasmid that expresses tLLO, an adjuvant (refer to Section 3.4.2), fused to 11 hotspot 
mutation peptide antigens and 11 sequence-optimized peptide antigens derived from TAAs. The 
TAA-derived peptide antigens expressed by the ADXS-503 construct were selected based on their 
binding affinity to 4 common HLA alleles, which cover >90% of patients with NSCLC in North 
America and Western Europe. 
The 11 shared hotspot mutation peptide antigens are from 7 genes and represent the most frequent 
somatic alterations in a proprietary mutational database from over 600 patients with NSCLC. 
These hotspot mutations occur in oncogenic driver genes, such as KRAS and PIK3CA, and in tumor 
suppressor genes such as TP53. Approximately 42% of patients with squamous or non-squamous 
NSCLC have at least one hotspot mutation that is targeted by ADXS-503. 
The 11 sequence-optimized TAA peptide antigens are derived from proteins, such as NY-ESO-1 
and CEACAM5, that have been shown to be immunogenic in NSCLC patients. The sequence-
optimized TAA-derived peptide antigens have been selected for wide expression across NSCLC 
tumors, with 7 of the selected TAA-derived peptide antigens expressed in all patients with NSCLC. 
These peptides have been sequence-optimized to increase binding affinity to the most common 
HLA types in North America and Western Europe. Enhancing peptide binding to a specific MHC 
class I allele increases the potential for recognition by tumor-specific T cells. 
Please refer to the ADXS-503 IB for additional details on the ADXS-503 construct. 
3.4.2. Mechanism of Action 
As a live attenuated bacterium, the Lm-based vector is rapidly taken up by APCs that recognize 
the bacteria as foreign. The uptake of the Lm-based vector results in the activation and maturation 
of not only the APC but also other innate immune cells through their recognition of Lm-specific 
PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular 
patterns). Once inside the APC, ADXS-503 can escape the phagosome and enter the cytosol, where 


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Protocol ADXS-503-101 
34 
it secretes fusion proteins consisting of tLLO attached to the selected hotspot mutation peptide 
antigens and sequence-optimized TAAs. These fusion proteins, along with other secreted Lm 
proteins, are transported to the proteasome and degraded into peptides that subsequently enter the 
MHC class I antigen presentation pathway. Not all bacteria, however, are able to escape the 
phagosome before phagosome-lysosome fusion. ADXS-503-derived proteins that are degraded 
into peptides in the phagolysosome gain access to the MHC class II antigen presentation 
pathway. The presentation of ADXS-503-derived peptides by MHC class I and class II molecules 
on the surface of activated APCs stimulates the generation of hotspot mutation- and 
TAA-specific CD4+ and CD8+ T cells and culminates in T cell infiltration and destruction of 
tumors expressing one or more of these antigens (Wood, 2014). 
In addition to the generation of antigen-specific T cell responses, treatment with Lm-based 
immunotherapies has been shown to reprogram the TME. First, administration of an Lm-based 
immunotherapy triggers the expression of chemokines and chemokine receptors that recruit 
effector T cells from tumor-draining lymph nodes into the core of the tumor (Guirnalda, 2013). 
Second, administration of an Lm-based immunotherapy reduces the relative number and 
suppressive function of intratumoral Tregs and MDSCs (Wallecha, 2013). Overcoming the 
immunosuppressive TME that often characterizes solid tumors in patients with advanced cancers, 
such as metastatic NSCLC, is critical to enabling an effective immunologic response to the cancer. 
An increase in the ratio of CD8+ tumor-infiltrating leukocytes to Tregs, as a result of the 
administration of an Lm-based immunotherapy, has been observed in a variety of mouse tumor 
models (Chang, 2014). Finally, in preclinical studies, Lm-based immunotherapies induced the 
expression of PD-L1 on both tumor cells and tumor-infiltrating macrophages in a HPV+ murine 
tumor model that normally does not express PD-L1 (Figure 3). Therefore, Lm-based 
immunotherapies have been shown to reprogram the TME and to convert a nonimmunogenic 
“cold” tumor to an immunogenic “hot tumor”. This supports the combination of Lm-based 
immunotherapies with immune checkpoint inhibitors, as described in Section 3.4.5.1. 


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35 
 
Figure 3. Lm-based immunotherapies induce expression of PD-L1 on tumor cells and tumor-infiltrating 
macrophages in a HPV+ murine tumor model. 
C57BL/6 mice were implanted with 1x105 HPV+ TC-1 tumor cells in the hind flank. Tumor-bearing mice were then 
treated on Day 8 post-tumor implantation with phosphate buffered saline (PBS) or ADXS11-001 (Lm vector 
expressing the full length E7 protein of HPV 16) and at 7-day intervals thereafter for a total of 3 doses. Tumors were 
harvested on Day 24 post-implantation, embedded in OCT compound, sectioned, and then stained with antibodies 
against PD-L1 (red) and the macrophage marker F4/80 (green) for immunofluorescence microscopy. A) PD-L1 (red) 
expression is detected in tumors of ADXS11-001-treated mice but not in tumors of PBS-treated mice. B) In the tumors 
of ADXS11-001 treated mice, PD-L1 expression is detected on both TC-1 tumor cells (examples highlighted with red 
arrows) and tumor-infiltrating macrophages (examples highlighted with yellow arrows). 
Please refer to the ADXS-503 IB for additional details on the mechanisms of action of Advaxis’ 
Lm-based immunotherapies. 
3.4.3. Nonclinical Studies with ADXS-503 
The ability of ADXS-503 to inhibit tumor growth was evaluated in the CT26 mouse tumor model, 
which expresses the G12D hotspot mutation in Kras. Eight-week-old female BALB/c mice (n=40) 
were injected subcutaneously with 3x105 CT26 tumor cells in the hind flank on Day 0. Mice (n=10 
per group) subsequently received 1 of the following 4 treatments on Days 4, 11 and 18 post-tumor 
implantation: 
• Phosphate buffered saline (PBS; vehicle control); 
• 1x108 colony forming units (CFU) of LmddA-274, a non-TAA expressing Lm vector; 
• 1x108 CFU of ADXS-503; 
• 1x108 CFU of ADXS-Kras G12D, an Lm vector expressing only the Kras G12D 
mutation, as a 21-mer, from the ADXS-503 construct.  
Tumor growth was monitored by measuring tumor volume twice weekly for 24 days after tumor 
implantation. See Figure 4A for the experimental design. 
DAPI
F4/80
PD-L1
PBS
ADXS11-001
DAPI
F4/80
PD-L1
PD-L1+ Tumor cell
PD-L1+ Macrophage (F4/80+)
ADXS11-001-treated
A
B


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Protocol ADXS-503-101 
36 
  
Figure 4. Both ADXS-503 and ADXS-Kras G12D, an Lm-based vector targeting a single Kras hotspot mutation, 
significantly inhibit the growth of CT26 tumors.    
A) BALB/c mice were implanted with 3x105 CT26 tumor cells in the hind flank. Tumor-bearing mice were then 
treated on Day 4 post-tumor implantation with PBS, LmddA-274 (empty Lm vector control), ADXS-503 or 
ADXS-Kras G12D (Lm vector expressing the Kras G12D mutation as a 21mer) and at 7-day intervals thereafter for 
a total of 3 doses. Tumor volume was measured twice a week. B) tumor growth curves for all treatment groups.  
****P< .0001. Data are representative of 2 independent experiments. 
As shown in Figure 4B, ADXS-503 significantly delayed tumor growth compared with control 
groups (PBS and LmddA-274), demonstrating the potential for ADXS-503 to prime an effective 
anti-tumor immune response against tumors that harbor at least 1 antigen expressed by the 
ADXS-503 construct.  In addition, the anti-tumor activity of ADXS-Kras G12D was equivalent to 
that of ADXS-503, indicating that a peptide antigen derived from a single hotspot mutation and 
expressed by an Lm-based vector can inhibit tumor growth. 
Please refer to the ADXS-503 IB for additional details on the anti-tumor activity of ADXS-503 in 
the CT26 tumor model experiments. The IB also describes other nonclinical studies with Lm-based 
immunotherapies that support the use of ADXS-503 in humans. 
3.4.4. Clinical Experience with ADXS-503 
3.4.4.1. Clinical Safety with ADXS-503 
This is the first study of ADXS-503 in the clinic where humans were dosed, and therefore, clinical 
data are limited. However, because Advaxis Lm-based immunotherapies share a common platform 
and are bioengineered and manufactured in a similar manner, the clinical safety profile of 


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Protocol ADXS-503-101 
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ADXS-503 is expected to be similar to that of other Lm-based immunotherapies. Therefore, the 
following clinical safety data across the Advaxis Lm immunotherapy platform is presented. 
As of November 2020, clinical safety data are available for 540 subjects enrolled in 14 clinical 
studies with Advaxis Lm-based immunotherapies including ADXS-HPV (ADXS11-001), 
ADXS-PSA (ADXS31-142), and ADXS-NEO. These agents have been evaluated in subjects with 
human papillomavirus (HPV)-associated cancers, prostate cancer, metastatic solid tumors, and in 
personalized Lm-based cancer immunotherapy, respectively. A total of over 1,500 doses have been 
administered to subjects at doses ranging from 5x107 to 1x1010 CFU every 3 or 4 weeks. Overall, 
Advaxis Lm-based immunotherapies have been safe and well-tolerated. 
The toxicity induced by Lm-based immunotherapies is a consequence of activation of the innate 
immune system shortly after treatment infusion. The specific treatment-induced signs and 
symptoms are caused by the interaction of the innate immune system with the Lm bacteria. Since 
the core Lm structure of Lm-based immunotherapies is the same, these agents should produce the 
same pattern of toxicity. The adaptive immune response is not expected to be different because 
Lm-based immunotherapies will induce T cell responses against Lm- and tumor-specific antigens, 
but not against normal host tissue. In other words, since the antigenic peptides expressed by 
ADXS-503 are derived from hotspot mutations or OFAs/CTAs present in NSCLC cells, 
ADXS-503 is not expected to induce reactivity with normal tissue. 
From clinical experience with Lm-based immunotherapies, a clear pattern of treatment-related AEs 
(TRAEs) has emerged, which is consistent with immune cell activation. The AEs typically consist 
of transient Grade 1-2 (mild-moderate) AEs such as chills, pyrexia, nausea, vomiting, fatigue, 
headache, tachycardia and hypotension, and appear during or shortly after treatment infusion. 
Grade 3 or Grade 4 hypotension is a manageable Event of Special Interest that occurs in ~7% of 
subjects treated with Lm-based immunotherapy. The symptoms usually resolve within 2 to 4 hours 
after infusion without specific intervention or respond rapidly to limited symptomatic treatment 
within 30 minutes to 1 hour. To date, there is no evidence of cumulative toxicity with subsequent 
dosing of Lm-based immunotherapy. Moreover, since incorporating a mandatory pre-infusion 
regimen into clinical trials, including adequate hydration, NSAIDs, antihistamines and antiemetics 
as key components, the incidence of acute signs and symptoms during or after treatment infusion, 
has been reduced. 
The largest clinical experience with Lm-based immunotherapies is in 478 subjects treated with 
ADXS11-001, alone or in combination with other agents. Treatment-related AEs with 
ADXS11-001 monotherapy in Advaxis Sponsored clinical trials, are shown in Table 1. Refer to 
the ADXS-503 IB for safety data across the Advaxis Lm-based immunotherapy platform. 


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Protocol ADXS-503-101 
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Table 1: Treatment-Related Adverse Events Reported ≥5% with ADXS11-001 Monotherapy 
in Advaxis Sponsored Trials 
 
n (%) Adverse Events 
(N=192)a 
System Organ Class 
 
Preferred Term 
All Grades 
Grade 3 or 4 
Cardiac disorders 
 
 
 
Tachycardia 
15 (7.8%) 
0 
Gastrointestinal disorders 
 
 
 
Diarrhoea 
10 (5.2%) 
1 (0.5%) 
 
Nausea 
54 (28.1%) 
0 
 
Vomiting 
48 (25.0%) 
1 (0.5%) 
General disorders and administration site 
conditions 
 
 
 
Chills 
91 (47.4%) 
0 
 
Influenza like illness 
11 (5.7%) 
0 
 
Pain 
10 (5.2%) 
0 
 
Pyrexia 
70 (36.5%) 
3 (1.6%) 
Immune system disorders 
 
 
 
Cytokine release syndrome 
15 (7.8%) 
7 (3.6%) 
Investigations 
 
 
 
Aspartate aminotransferase increased 
13 (6.8%) 
0 
 
Blood alkaline phosphatase increased 
11 (5.7%) 
2 (1.0%) 
 
Gamma-glutamyltransferase increased 
15 (7.8%) 
3 (1.6%) 
Metabolism and nutrition disorders 
 
 
 
Decreased appetite 
10 (5.2%) 
0 
Musculoskeletal and connective tissue disorders 
 
 
 
Back pain 
12 (6.3%) 
0 
 
Myalgia 
12 (6.3%) 
0 
Nervous system disorders 
 
 
 
Dizziness 
14 (7.3%) 
0 
 
Headache 
41 (21.4%) 
0 
Vascular disorders 
 
 
 
Hypotension 
46 (24.0%) 
12 (6.3%) 
a Subjects who were dosed on or before 22 Dec 2017, including 24 subjects from study ADXS001-02 which had a 
2:1 randomization between ADXS11-001 and placebo. 
Note: Adverse events with onset on or before 22 Dec 2017 are included. 
 
The Phase 1 study of ADXS-NEO (ADXS-NEO-02), a fully personalized Lm-based 
immunotherapy that expresses somatic mutation-derived neoantigens specific to each subject’s 
tumor, is completed. Data are available for 2 subjects treated during the dose-escalation portion of 
the study at dose level 1 (1x109 CFU). Of these 2 subjects, as of August 2018, 1 subject with 
NSCLC experienced Grade 3 hypoxia and 1 subject with colorectal cancer experienced Grade 3 
hypotension and Grade 3 hypoxia post-administration of the second dose. These events were 


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Protocol ADXS-503-101 
39 
reported after the second dose of ADXS-NEO in both cases. The event of Grade 3 hypotension 
resolved within the first 24 hours, while both cases of Grade 3 hypoxia were more persistent, 
resolving in a few days. Prior medications and comorbidities were confounding factors in the 
genesis of hypoxia. Subsequently, 3 subjects completed ADXS-NEO therapy at 1×108 CFU dosing 
level; this dose was well-tolerated for subjects with advanced or metastatic solid tumors.  
High-grade (≥ Grade 3) hypotension and/or hypoxia are considered Events of Special Interest with 
Lm-based immunotherapy treatment. An updated algorithm for the management of high-grade, 
acute toxicities during or after treatment infusion (including hypotension, hypoxia, 
encephalopathy, and organ toxicity) can be found in Appendix 7. 
Although rare, there have been two (2) reported cases of listeremia, in which attenuated Lm was 
found to be growing on implanted medical devices after the completion of study treatment. As a 
key safety measure with Lm-based immunotherapies, a 7-day course of post-infusion antibiotics 
are administered to ensure the clearance of Lm. Additionally, following the final dose of treatment, 
a 3-week course of antibiotics is administered to ensure the clearance of Lm (see Section 9.2.1.3 
for additional details). Furthermore, clinical trials with Lm-based immunotherapies prohibit the 
enrollment of subjects with implantable medical devices that can serve as a nidus of infection, 
further mitigating the risk of listeremia. 
In the Phase 1 study for ADXS11-001 (n=15 subjects), Lm was not detected in the blood of any 
subject beyond 48 hours post dose. Additionally, in the absence of post-infusion antibiotic 
treatment, Lm was not shed in the urine or feces of any subject at the highest dose level tested 
(1x1010 CFU) (Maciag, 2009). ADXS-503 is expected to have the same profile as ADXS11-001 
in this regard. 
Preliminary data from the ongoing ADXS-503-101study shows that ADXS-503 either alone (Part 
A) or in combination with Pembrolizumab (Part B-DL1 and Part C) appears to be safe and 
tolerable. Transient Grade 1–2 adverse events like fever, chills, and nausea were common after the 
infusion of ADXS-503. In 16 patients so far evaluated in the ongoing study, 7 treated with ADXS-
monotherapy (1x108 and 5x108 CFU) and 9 in combination with ADXS-503 (1x108 CFU) with 
pembrolizumab, there have been no dose-limiting toxicity events or events of high grade (eg, 
hypotension or hypoxia) as observed in the past at higher doses with other Lm constructs (Table 2). 


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Table 2: Treatment-Related Adverse Events, All Treated 
 
Part A 
Part A  
DL1 + DL2  
(N=7) 
Part B  
Dose Level 1  
(N= 7) 
Part C  
Dose Level 1 
 (N=2) 
DL  1 
(N=4) 
D L  2 
(N=3) 
≥ Grade 3 events  
Infusion related reaction 
0 
1 (33.33) 
1 (14.28) 
0 
0 
Grade 1 & 2 
Pyrexia 
0 
1 (33.33) 
1 (14.28) 
2 (28.57) 
0 
Chills 
0 
1 (33.33) 
1 (14.28) 
2 (28.57) 
0 
Influenza like illness 
0 
1 (33.33) 
1 (14.28) 
0 
0 
Nausea 
0 
1 (33.33) 
1 (14.28) 
0 
0 
Back pain 
0 
1 (33.33) 
1 (14.28) 
0 
0 
Neck pain 
0 
1 (33.33) 
1 (14.28) 
0 
0 
Rash 
0 
1 (14.28) 
0 
Acute kidney injury 
0 
1 (33.33) 
1 (14.28) 
0 
0 
Alanine aminotransferase 
increased 
0 
1 (33.33) 
1 (14.28) 
0 
0 
Aspartate aminotransferase 
increased 
0 
1 (33.33) 
1 (14.28) 
0 
0 
DL = Dose Levele. Comment about “Acute Kidney Injury” and elevation of liver enzymes were transient and in 
different patients and in all cases, patients recovered after brief hospitalization?  
 
Please refer to the ADXS-503 IB for additional details on the clinical experience with Lm-based 
immunotherapies. 
3.4.4.2. Clinical Efficacy with ADXS-503 
ADXS-503 has not previously been administered to humans, and therefore, clinical efficacy data 
is not yet available. 


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Protocol ADXS-503-101 
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3.4.5. Combination of Lm-Based Immunotherapy with an Immune 
Checkpoint Inhibitor 
3.4.5.1. Rationale for Combining Lm-Based Immunotherapy with an 
Immune Checkpoint Inhibitor 
ADXS-503 and immune checkpoint inhibitors have complementary mechanisms of immune 
activation and reversal of immune tolerance (see Section 3.3 and Section 3.4). ADXS-503 induces 
the generation of tumor-specific T cells, whereas pembrolizumab inhibits the PD-1/PD-L1 
checkpoint, allowing the T cells to engage in a more sustained attack against the tumor. Therefore, 
combining both agents in a dual-treatment approach, has the potential to provide synergistic anti-
cancer activity. 
As described in Section 3.4.2, Lm-based immunotherapies elicit innate immunity, generate 
antigen-specific T cell responses and reprogram the TME. Specifically, Lm-based 
immunotherapies 1) trigger the expression of chemokines and chemokine receptors that recruit 
effector T cells from tumor-draining lymph nodes into the tumor core; 2) reduce the frequencies 
and function of immunosuppressive Tregs and MDSCs in the TME; and 3) induce the expression 
of PD-L1 in the TME (Chang 2014; Guirnalda 2013; Wallecha 2013). These are hallmark 
characteristics of an immunogenic or “hot” tumor and provide support for the combination of 
ADXS-503 with PD-1/PD-L1 checkpoint inhibitors (Sharma, 2015). 
In a non-randomized clinical trial, the combination of ADXS-PSA with pembrolizumab in subjects 
with metastatic castrate-resistant prostate cancer (mCRPC) produced a 56.8% rate of disease 
control, whereas ADXS-PSA produced a 38.5% rate of disease control (Stein, 2018). These 
findings included stabilization of disease in subjects who presented with non-measurable disease 
(either soft tissue disease, bony disease, or both). Notably, PDCD1 (PD-1) and CD274 (PD-L1) 
expression were upregulated in PBMCs following a single dose of ADXS-PSA in this trial 
(Advaxis Internal Data). These results suggest that the upregulation of PD-L1 expression may be 
a key mechanism through which Lm-based immunotherapies can achieve clinical synergy when 
administered in combination with PD-1/PD-L1 checkpoint inhibitors. Furthermore, an optimal 
combination strategy may be to prime T cell immunity and induce the upregulation of PD-L1 
expression before administering the first dose of a PD-1/ PD-L1 checkpoint inhibitor. 
Please refer to the ADXS-503 IB for additional details. 
3.4.5.2. Safety of Lm-Based Immunotherapy with an Immune 
Checkpoint Inhibitor 
The known toxicity profile of Lm-based immunotherapies is generally non-overlapping with that 
of immune checkpoint inhibitors. In clinical trials combining Lm-based immunotherapies with 
immune checkpoint inhibitors, treatment has been generally well-tolerated. The toxicities observed 


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Protocol ADXS-503-101 
42 
with Lm-based agents have been distinct from those observed with immune checkpoint inhibitors, 
both in terms of the timing of the onset of toxicity and the nature of the toxicity. For example, in 
a clinical trial combining ADXS-PSA with pembrolizumab in 37 subjects with mCRPC, the 
observed TRAEs were as expected relevant to each agent’s individual safety profile, but no 
additive toxicities were observed as a result of the combination (Table 3). In this trial, ADXS-PSA 
was administered as monotherapy in Part A at escalating doses of 1x109 CFU, 5x109 CFU and 
1x1010 CFU every 3 weeks. In Part B, ADXS-503 was administered at 1x109 CFU in combination 
with 200 mg of pembrolizumab every 3 weeks for 3 doses, followed 3 weeks later by 200 mg of 
pembrolizumab alone, in a 12-week cycle. The 12-week cycle repeated until treatment 
discontinuation. 
Table 3: Treatment-Related Adverse Events >10% with ADXS-PSA Alone (Part A) and in 
Combination with Pembrolizumab (Part B) in Metastatic Castrate-Resistant Prostate 
Cancer (mCRPC) 
Treatment Related Adverse 
Event (TRAE) 
 
System Organ Class  
Preferred Term 
Grade 1-2 
Grade 3 
  
Part A   
(N=13) 
Part B 
(N=37) 
Part A 
(N=13) 
Part B 
(N=37) 
Subjects with ≥1 TRAE; n (%) 
13 (100%) 
36 (97%) 
5 (38.5%) 
13 (35.1%) 
TRAEs occurring in ≥10% of subjects (Part A + Part B) 
Chills 
7 (53.8%) 
25 (67.6%) 
0  
0  
Rigors 
6 (46.2%) 
21 (56.8%) 
1 (7.7%) 
0  
Fever 
8 (61.5%) 
19 (51.4%) 
0  
1 (2.7%) 
Nausea 
5 (38.5%) 
14 (37.8%) 
0  
0  
Fatigue 
4 (30.8%) 
10 (27.0%) 
1 (7.7%) 
3 (8.1%) 
Hypertension 
0  
5 (13.5%) 
2 (15.4%) 
7 (18.9%) 
Hypotension 
4 (30.8%) 
7 (18.9%) 
1 (7.7%) 
1 (2.7%) 
Pain (all) 
2 (15.4%) 
11 (29.7%) 
0  
0  
Anemia 
0  
4 (10.8%) 
1 (7.7%) 
3 (8.1%) 
Vomiting 
2 (15.4%) 
4 (10.8%) 
0  
0  
Sinus tachycardia 
2 (15.4%) 
3 (8.1%) 
1 (7.7%) 
0  


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Protocol ADXS-503-101 
43 
Treatment Related Adverse 
Event (TRAE) 
 
System Organ Class  
Preferred Term 
Grade 1-2 
Grade 3 
  
Part A   
(N=13) 
Part B 
(N=37) 
Part A 
(N=13) 
Part B 
(N=37) 
Subjects with ≥1 TRAE; n (%) 
13 (100%) 
36 (97%) 
5 (38.5%) 
13 (35.1%) 
TRAEs occurring in ≥10% of subjects (Part A + Part B) 
Dyspnea 
1 (7.7%) 
4 (10.8%) 
0  
1 (2.7%) 
Diarrhea 
1 (7.7%) 
3 (8.1%) 
0  
1 (2.7%) 
Headache 
1 (7.7%) 
4 (10.8%) 
0  
0  
Decreased appetite 
0  
5 (13.5%) 
0  
0  
Hypothyroidism 
0  
5 (13.5%) 
0  
0  
 
One Grade 5 toxicity has been reported following treatment with ADXS11-001 in combination 
with the PD-L1 inhibitor, durvalumab. Prior to the event, a 37 -year--old female subject with 
metastatic cervical cancer had been treated with 20 doses of durvalumab and 10 doses of ADXS11-
001 over the course of approximately 9 months. The subject developed severe hypotension after 
the infusion of durvalumab and ADXS11-001 and subsequently died of acute respiratory failure 
secondary to pulmonary edema and diffuse cerebral edema with bilateral herniation of the uncus 
and cerebellar tonsils. The autopsy report indicated that the subject had areas of dense pulmonary 
fibrosis, but it is unknown whether the presence of fibrosis in the lung contributed to the event. An 
updated algorithm for the management of high-grade, acute toxicities during or after treatment 
infusion (including hypotension, hypoxia, encephalopathy, and organ toxicity), has been 
developed as a result of this event (see Appendix 7). Furthermore, the subject ID card provided to 
study subjects during Screening must specify that the subject is enrolled in a clinical trial of an 
experimental agent that may be associated with immune-mediated toxicity, induced by Lm. 
Please refer to the ADXS-503 IB for additional details. 
3.5. 
Study Rationale and Selected Patient Population 
Over the past decade and a half, several TKIs and immune checkpoint inhibitors have been 
approved to treat patients with metastatic NSCLC, improving the overall therapeutic 
armamentarium (see Section 3.2 and Section 3.3). Unfortunately, the majority of known driver 
mutations are not targets for approved TKIs, and even in the subset of patients harboring an 


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Protocol ADXS-503-101 
44 
actionable mutation, drug resistance ultimately develops, leading to disease progression in 
approximately 10-19 months Chan 2015; Hirsh 2018; NCCN, 2018; Soria, 2018; Zappa 2016).  
Furthermore, fewer than 20% of patients treated with immune checkpoint inhibitors derive long-
term clinical benefit. For example, in patients with high PD-L1 expression who receive 
pembrolizumab as monotherapy in the first-line setting, the ORR is less than 50% and most 
patients experience disease progression in approximately 10-12 months (Brahmer 2017; Reck 
2016). Furthermore, data from Keynote 189, Keynote 407, IMpower 150, IMpower 131 and 
CheckMate 227 clinical trials in the first-line setting show that approximately 50-60% of patients 
experience disease progression within one year of combination therapy with PD-1/ PD-L1 
checkpoint inhibitors, regardless of the agents used (eg, VEGF inhibitor, ipilimumab and/or 
chemotherapy) (Gandhi 2018; Hellmann 2018; Jotte 2018; Paz-Ares 2018; Socinski 2018). 
Therefore, a clear unmet need remains for new treatment strategies for patients with metastatic 
NSCLC. 
An important aspect of treatment with checkpoint inhibitors such as pembrolizumab, is the option 
to confirm apparent disease progression by repeating the tumor evaluation at originally scheduled 
approximately between 4 to 8 weeks after the first evidence of progression is expanded based on 
input from treating physicians. This is based on the observation that response patterns may be 
atypical in the context of immunotherapy. Apparent disease progression may not be confirmed 
after a subsequent assessment; therefore, it is appropriate to continue therapy while awaiting 
confirmation of disease progression. Stable subjects may be treated beyond confirmed progression 
in situations where the investigator determines that the subject is deriving clinical benefit. The 
iRECIST guidelines also provide a method for making treatment decisions in the context of 
confirmation of PD assessment. 
This approach to managing checkpoint inhibitor treatment means that the introduction of a new 
treatment intervention may be able to delay the process of disease progression.  The time interval 
prior to PD confirmation provides an opportunity to evaluate an investigational agent prior to the 
development of confirmed disease progression and allows the treating physician to independently 
assess the clinical status of the patient for possible benefit with treatment under this study. 
ADXS-503 is a novel Lm-based immunotherapy, bioengineered to elicit potent T cell responses 
against 22 tumor antigens that include 1) 11 peptide antigens derived from frequently occurring 
and commonly shared hotspot mutations in patients with squamous and non-squamous NSCLC 
and 2) 11 peptide antigens derived from sequence-optimized TAAs that are differentially 
expressed or overexpressed in NSCLC tumors (see Section 3.4.1 and Section 3.4.2). ADXS-503 
is designed to express multiple tumor antigen targets to which patients may generate a broad set 
of effector T cells for tumor control. Similar to other Lm-based immunotherapies, ADXS-503 has 
the potential to reduce immunosuppressive Treg and MDSC frequencies and function within the 


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Protocol ADXS-503-101 
45 
TME and has the potential for clinical synergy when used in combination with immune checkpoint 
inhibitors (see Section 3.4.2 and Section 3.4.5). Furthermore, ADXS-503, which includes the 
KRAS G12D hotspot mutation peptide antigen, has demonstrated activity in a mouse Kras G12D 
tumor model (see Section 3.4.3). The multi-target ADXS-503 construct effectively suppressed 
tumor growth and demonstrated efficiency in eliciting anti-tumor activity. Therefore, ADXS-503 
represents a new treatment approach for patients with metastatic NSCLC, with the potential for 
durable anti-tumor activity and long-term clinical benefit when used alone or in combination with 
standard of care agents such as immune checkpoint inhibitors. 
The purpose of this first-in-human clinical study is to evaluate the safety, tolerability and 
clinical/immunological activity of ADXS-503 as monotherapy and in combination with 
pembrolizumab in subjects with metastatic squamous or non-squamous NSCLC. This study will 
be performed in 2 phases, a safety phase and an efficacy phase. 
Safety Phase 
In the safety phase, ADXS-503 will be administered as monotherapy in Part A and in combination 
with pembrolizumab in Part B. 
Part A will enroll subjects in a refractory setting, who have previously received, and then 
progressed or been intolerant to up to 3 lines of prior therapy for metastatic NSCLC, including 
approved chemotherapy, targeted therapy, immunotherapy and antibody therapy, if eligible. 
Subjects will be enrolled in Part A irrespective of PD-L1 expression or EGFR or ALK mutation 
status. However, subjects with an EGFR sensitizing mutation or ALK translocation must have 
received and then progressed or been intolerant to at least 1 prior line of approved targeted therapy 
to be eligible for Part A. In this patient population, ADXS-503 monotherapy has the potential to 
provide clinical benefit when compared to salvage treatments such as single-agent docetaxel or 
pemetrexed. 
Part B will enroll subjects with metastatic NSCLC who meet the following criteria: 
• Are undergoing treatment with pembrolizumab monotherapy or combination therapy with 
pembrolizumab + platinum-based chemotherapy or are receiving pembrolizumab + 
pemetrexed as maintenance therapy, as last treatment for metastatic NSCLC 
• The subject’s most recent tumor assessment is consistent with PD according to RECIST v1.1 
• There is no evidence of rapid disease progression or clinical deterioration that would 
preclude continuation of pembrolizumab treatment for up to 12 weeks before ADXS-503 is 
added-on 
• Subjects must consent to allow the acquisition of fresh or archival formalin-fixed paraffin-
embedded (FFPE) tumor tissue, either a block or unstained slides along with matching blood at 


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Protocol ADXS-503-101 
46 
baseline for performance of sequencing analysis.   
• In Part B, subjects must receive the first dose of ADXS-503 within 12 weeks of the initial 
tumor assessment showing PD (while on last treatment with pembrolizumab monotherapy or 
pembrolizumab + platinum-based chemotherapy or pembrolizumab + pemetrexed as 
maintenance therapy). ADXS-503 will be administered as add-on treatment to the ongoing 
pembrolizumab therapy. 
• Subjects who are receiving pembrolizumab in combination with platinum-based 
chemotherapy or pembrolizumab with pemetrexed as maintenance therapy, will continue on 
pembrolizumab monotherapy every 3 weeks per schedule while other drugs are washed-out 
for 3 weeks. 
Efficacy Phase  
In the efficacy phase (Part B), expansion of the Part B-dose level 1 cohort will enroll subjects 
with metastatic squamous or non-squamous NSCLC who meet the same criteria as Part B dose 
escalation mentioned above. Based on Stage I of Simon’s Two-stage design, 18 patients will be 
accrued in this study arm. Sponsor may decide to accrue additional 25 subjects for a total of 43 
patients in Stage II. Accrual of patients to Part B dose level 2 (ADXS-503 at 5x108 CFU in 
combination with 200 mg pembrolizumab) is pending Sponsor decision to commence. 
In the efficacy phase (Part C), ADXS-503 will be administered in combination with 
pembrolizumab in subjects who have received no prior systemic treatment for metastatic NSCLC, 
and who will be treated in accordance with the approved Product Label for pembrolizumab 
monotherapy in the first-line setting. Clinical site must provide documentation of tumor PD-L1 
expression and EGFR mutation and/or ALK translocation status as evaluated by FDA-approved 
tests in all patients in Part C. Baseline tumor samples must express PD-L1 [Tumor Proportion 
Score (TPS) ≥1% as determined by an FDA-approved test], with no EGFR or ALK genomic tumor 
aberrations for subjects to be eligible for Part C. The rationale for enrolling subjects in a first-line 
setting in Part C, is based on the principle of cancer immunotherapy that treatment may be less 
effective as a patient receives more lines of therapy. This would make detection of an efficacy 
signal more difficult. An earlier line of treatment makes sense because it provides an improved 
setting for detecting clinical activity. 
Study objectives are described in Section 4. See Section 5.1 for a full description of the study 
design. 


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Protocol ADXS-503-101 
47 
3.6. 
Overall Benefit/ Risk Assessment 
3.6.1. Potential Benefits 
ADXS-503 expresses a total of 22 NSCLC-associated tumor antigens, whose selection ensures 
that 42% of patients with NSCLC will express at least one of the targeted hotspot mutation peptide 
antigens and that >90% will express at least one of the TAAs targeted by the sequence-optimized 
TAA peptide antigens. The delivery of multiple tumor antigens increases the likelihood of immune 
recognition of tumor cells, leading to potential clinical efficacy. In addition to stimulating an anti-
tumor immune response, Advaxis’ Lm based immunotherapies reduce the frequencies and function 
of immunosuppressive Tregs and MDSCs within the TME, and upregulate the expression of 
PD-L1 (Advaxis Internal Data; Chang 2014; Guirnalda 2013; Wallecha 2013). This 
reprogramming of the TME increases the susceptibility of the tumor to immune attack and 
provides the potential for synergistic activity when ADXS-503 is used in combination with 
PD-1/PD-L1 immune checkpoint inhibitors.  Based on these properties, ADXS-503 represents a 
new treatment approach for patients with metastatic NSCLC, with the potential for clinical benefit 
when used alone or in combination with an immune checkpoint inhibitor such as pembrolizumab. 
3.6.2. Potential Risks 
3.6.2.1. Potential Risks with ADXS-503 
3.6.2.1.1.  Risks Associated with Treatment Infusion 
The clinical safety profile of ADXS-503 is expected to be similar to that of other Lm-based 
immunotherapies, as described in Section 3.4.4. The safety profile of these agents primarily 
consists of Grade 1-2 “flu-like” symptoms (eg, chills, pyrexia, nausea, vomiting, fatigue, headache, 
tachycardia and hypotension) that last 2 to 4 hours after treatment infusion and are consistent with 
immune cell activation, induced by Lm. These symptoms usually resolve without specific 
intervention or respond rapidly to limited symptomatic treatment within 30 minutes to 1 hour. 
As a prophylaxis for acute symptoms which may occur during or after treatment infusion, a 
mandatory pre-infusion regimen of adequate hydration, NSAIDs, antihistamines and antiemetics, 
has been incorporated into Lm-based immunotherapy treatment regimens. In addition, a key aspect 
of risk mitigation is that following each ADXS-503 infusion, all subjects will be observed in the 
clinic and will have vital signs, including oxygen saturation, monitored for at least 4 hrs. 
In some instances (<7%), Grade 3-4 hypotension has been observed following treatment with Lm-
based immunotherapy, either as monotherapy or in combination with immune checkpoint 
inhibitors. Elevated IL-6 and other cytokine levels have been observed after infusion of Lm-based 
immunotherapy, with peak levels occurring 2 to 4 hours after infusion. Increased levels of IL-6 


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Protocol ADXS-503-101 
48 
has been strongly associated with capillary leak, which manifests as hypotension. Emerging 
evidence indicates that IL-6 antagonists, such as tocilizumab, have demonstrated good results in 
treating IL-6-induced hypotension, and is therefore recommended for cases of severe hypotension 
refractory to supportive care (eg, fluids and/or pressors) early in the course of the event (Actemra®, 
2020; Grupp, 2013; Herceptin®, 2020; Lee, 2014; Winkler, 1999). 
Investigators will use their best judgement to appropriately code and treat individual AEs that 
occur during or after infusion, rather than grouping them into broad categories, such as “infusion 
reaction” or “cytokine release syndrome”, so that specific management strategies can be applied, 
as appropriate. For example, a clinically suspected high-grade infusion reaction may only be 
related to anaphylaxis with hives and angioedema which can be treated with diphenhydramine/ 
steroids, while a high-grade hypotension may require tocilizumab ± steroids after failing to be 
controlled with saline boluses. Hypersensitivity/ anaphylactic events during or after the infusion, 
should be managed according to the guidelines provided in Appendix 6. An updated algorithm for 
the management of other acute AEs, including hypotension, hypoxia, encephalopathy, organ 
toxicity, fever and constitutional symptoms is provided in Appendix 7. 
As described in Section 3.4.4.1, a subject with NSCLC experienced Grade 3 hypoxia and a subject 
with colorectal cancer experienced Grade 3 hypotension and Grade 3 hypoxia following the second 
dose of ADXS-NEO (dose of 1x109 CFU). Furthermore, as described in Section 3.4.5.2, a Grade 
5 acute respiratory failure event has been reported following treatment with ADXS11-001 and 
durvalumab. The algorithm in Appendix 7 has subsequently been updated to provide management 
guidelines for high-grade toxicities considered Events of Special Interest, including Grade 3 or 4 
hypotension, hypoxia, encephalopathy and organ toxicity (see Section 9.1.5). Furthermore, the 
subject ID card provided to study subjects during Screening must specify that the subject is 
enrolled in a clinical trial of an experimental agent that may be associated with immune-mediated 
toxicity induced by Lm. 
As of April 2021, nineteen subjects have been treated with ADXS 503 in the ongoing ADXS_503-
101 study: seven as monotherapy and 12 in combination with pembrolizumab or with ADXS-503 
alone. TheADXS-503 in combination continues to be safe and tolerable without inducing high 
grade toxicity of added doses being administered. See Table 3.  
3.6.2.1.2.  Risks Associated with Immune-Related Adverse Events 
While the hotspot mutation peptide antigens and TAAs expressed by the Lm construct are not 
expected to induce or exacerbate autoimmune toxicities, the potential for sub-acute or late- 
occurring immune-related AEs exists. Therefore, immune-related AEs will be closely monitored 
for in this study, with ADXS-503 as a single agent, and in combination with pembrolizumab. 
General guidance for treating immune-related AEs considered by the Investigator to be associated 
with ADXS-503, is provided in Appendix 8. 


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Protocol ADXS-503-101 
49 
3.6.2.1.3.  Risks Associated with Listeremia 
ADXS-503 is a live attenuated Lm-based immunotherapy. A safety consideration is the 
administration of live attenuated Lm to potentially immunocompromised subjects who may have 
previously received heavy doses of radiation and chemotherapy. In preclinical studies, attenuated 
Lm strains from Advaxis were cleared within 48 hours in immunocompromised mouse models, 
such as SCID mice and IFNγ-deficient mice, in the absence of antibiotic treatment (Gunn, 2001). 
As described in Section 3.4.4, listeremia, although rare, has been reported in two subjects with 
implanted medical devices, who were treated with Lm-based immunotherapy. The risk of Lm 
biofilm formation will be mitigated in this study through the prohibition of the enrollment of 
subjects with implanted devices with such a risk and which cannot be removed easily. 
Additionally, the risk of the persistence of Lm will be mitigated through the use of a 7-day course 
of prophylactic antibiotics after each ADXS-503 infusion. Following the final dose of ADXS-503, 
a 3-week course of oral antibiotics will be administered to ensure the clearance of Lm (see 
Section 9.2.1.3 for additional details). 
Listeriosis (as opposed to listeremia with attenuated Lm) is a systemic organ infection caused by 
wild type, invasive Lm and is highly unlikely to occur during study treatment, because the method 
of attenuation used in the Advaxis Lm platform results in a greater than 4 log reduction in virulence 
compared to wild type Lm. 
Lm-based immunotherapy is rapidly cleared from the blood and no shedding in urine or feces is 
observed. In the Phase 1 study for ADXS11-001 (n=15 subjects), Lm was not detected in the blood 
of any subject beyond 48 hours post dose. Additionally, in the absence of post-infusion antibiotic 
treatment, Lm was not shed in the urine or feces of any subject at the highest dose level tested 
(1x1010 CFU) (Maciag 2009). Importantly, to date, no person-to-person transmission with Lm-
based immunotherapies has been reported. 
3.6.2.1.4.  Other Risks 
Although ADXS-503 is attenuated and nonpathogenic, all Lm strains are classified as biosafety 
level 2 (BSL-2) because the Centers for Disease Control and Prevention (CDC) do not provide 
differential classification for attenuated and wild-type bacterial agents. With proper PPE and 
hazardous waste disposal measures, nursing and pharmacy staff at over 50 global clinical research 
sites have handled Lm strains safely. Universal precautions and institutional guidelines should be 
used when handling investigational drugs and human specimens. While the administration of 
ADXS-503 is not expected to complicate wound healing, the effect of surgery itself may suppress 
the immune system and delay the healing process. Therefore, a subject may initiate or resume 
study treatment 2 weeks after minor surgery (ie, surgery involving little risk to the life of the 
subject; specifically, an operation on the superficial structures of the body or a manipulative 
procedure that does not involve a serious risk) if the wound has completely healed and there are 


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Protocol ADXS-503-101 
50 
no wound healing complications. A subject who has wound healing complications following minor 
surgery, received major surgery or requires new implants and/or devices (permitted by the protocol) 
during the course of the study, must wait a minimum of 6 weeks and must have recovered (eg, 
return to baseline or Grade ≤1) from any toxicity and/or complication before the next dose of study 
treatment. Sponsor consultation is required prior to resuming study treatment for these subjects. If 
study treatment is delayed beyond 12 weeks due to concomitant surgery, the subject may be 
discontinued from study treatment. 
As noted, ADXS-503 administration is safe, however, there may also be potential unknown risks 
and additional information about the known and expected risks of ADXS-503 can be found in the 
IB. Please refer to Section 9.2 for clinical safety management and supportive care guidelines for 
ADXS-503 treatment.  
3.6.2.2. Potential Risks with Pembrolizumab 
Please refer to the approved pembrolizumab Product Label for the known and expected risks of 
treatment with pembrolizumab. 
A pattern of immune-related AEs has been defined for pembrolizumab, for which management 
guidelines have been developed. These immune-related AEs include: pneumonitis, 
diarrhea/colitis, Type 1 diabetes mellitus (T1DM), hypophysitis, hyperthyroidism or 
hypothyroidism, primary adrenal insufficiency, hepatic AEs, renal failure/ nephritis, skin 
reactions, infusion reactions, hemophagocytic lymphohistiocytosis, complications of 
allogeneic hematopoietic stem cell transplant (HSCT), and hematological toxicity in patients 
with chronic Hodgkin lymphoma (cHL). Immune-mediated adverse reactions reported in less 
that 1% of patients treated with pembrolizumab include uveitis, myositis, Guillain-Barre 
syndrome, pancreatitis, encephalitis, sarcoidosis, myasthenic syndrome/myasthenia gravis and 
myocarditis. Guidelines for the management of common immune-related AEs are provided in 
Appendix 9. Refer to Appendix 6 for guidelines to manage infusion reactions associated with 
pembrolizumab. 


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Protocol ADXS-503-101 
51 
4. 
Study Objectives and Endpoints 
The objectives and endpoints for this study are outlined in the Table below. 
This study will enroll subjects with metastatic squamous or non-squamous NSCLC in a safety 
phase (Part A and Part B) and an efficacy phase (Part C). See Section 5.1 for details of the study 
design. 
• Safety phase (Part A and Part B): 
o Part A: ADXS-503 monotherapy at 2 escalating dose levels; Refractory setting. 
o Part B: ADXS-503 at 2 escalating dose levels + pembrolizumab; Enroll subjects 
undergoing treatment with pembrolizumab monotherapy who have an initial 
assessment of PD per RECIST v1.1 on the most recent tumor scan, and are awaiting 
a confirmatory scan 4-8 weeks later. ADXS-503 administered as add-on therapy to 
pembrolizumab. 
• Efficacy phase  
o Part B expansion: ADXS-503 at 1 x108 CFU+ pembrolizumab; Enroll subjects 
undergoing treatment with pembrolizumab monotherapy or receiving combination 
therapy with pembrolizumab + platinum-based chemotherapy or pembrolizumab + 
pemetrexed as maintenance therapy, as their last treatment in metastatic setting, and 
who have an initial assessment of PD per RECIST v1.1 on the most recent tumor 
scan. ADXS-503 administered as addon therapy to pembrolizumab. The 
administration of pembrolizumab is per the approved label and in the second year 
treating physicians can change dosing from Q3W to Q6W for both drugs. 
o Part C: ADXS-503 + pembrolizumab; Enroll subjects per the approved Product 
Label for pembrolizumab monotherapy in the first-line setting and in the second 
year treating physicians can change dosing from Q3W to Q6W for both drugs. 
 
See Section 3.5 and Section 6 for a description of the subject populations in Parts A, B, and C. 
Objectives 
Endpoints 
Primary 
1. To evaluate the safety and tolerability of 
ADXS-503, administered as monotherapy in 
Part A and in combination with 
pembrolizumab in Part B, and to determine 
the maximum tolerated dose (MTD) or 
maximum administered dose (MAD).  
 
1. Adverse events (AEs); dose-limiting toxicities 
(DLTs); physical examination findings; 
clinical laboratory values; vital sign 
measurements; and performance status 
monitoring. 
2. To characterize the preliminary anti-tumor 
activity of ADXS-503, administered in 
combination with pembrolizumab in Part B 
dose-expansion and Part C, per RECIST v1.1.  
 
2. Tumor response per RECIST v1.1, including: 
• Best overall response (BOR) 
• Objective response rate (ORR) 
• Disease control rate (DCR) 
• Duration of objective response (DOR) 
 


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Protocol ADXS-503-101 
52 
 
 
Secondary 
1. To characterize the preliminary anti-tumor 
activity of ADXS-503, administered as 
monotherapy in Part A and in combination 
with pembrolizumab in Part B dose-
escalation, per RECIST v1.1.  
 
1. Tumor response per RECIST v1.1, as 
described above.  
 
2. To determine the progression-free survival 
(PFS) and PFS rate at 12 months per RECIST 
v1.1, for subjects treated with ADXS-503 
monotherapy in Part A and ADXS-503 in 
combination with pembrolizumab in Part B 
and Part C. 
2. PFS and PFS rate at 12 months per RECIST 
v1.1. 
 
 
 
 
3. To determine overall survival (OS) and 6- and 
12-month milestone OS rates for subjects 
treated with ADXS-503 monotherapy in Part 
A and ADXS-503 in combination with 
pembrolizumab in Part B and Part C. 
3. OS; and 6- and 12-month milestone OS rates. 
4. To evaluate the safety and tolerability of 
ADXS-503 in combination with 
pembrolizumab in Part B dose-expansion and 
Part C. 
4. Safety and tolerability, as described above. 
 
 
Exploratory 
1. To characterize the preliminary anti-tumor 
activity of ADXS-503, administered as 
monotherapy in Part A and in combination 
with pembrolizumab in Part B and Part C, per 
iRECIST.  
 
1. Tumor response per iRECIST, including 
BOR, ORR, DCR and DOR. 
2. To determine PFS and PFS rate at 12 months 
per iRECIST, for subjects treated with ADXS-
503 monotherapy in Part A and ADXS-503 in 
combination with pembrolizumab in Part B 
and Part C. 
 
2. PFS and PFS rate at 12 months per iRECIST. 
3. To characterize the immunological activity of 
ADXS-503, administered as monotherapy in 
Part A and in combination with 
pembrolizumab in Part B; and to characterize 
the genomic profiles of study subjects. 
 
3. Immunological activity will be evaluated as 
follows: 
• In pre- and on-treatment blood samples: 
o Evaluate the changes in the states of 
activation and differentiation in various 
immune cells by flow cytometry, whole 
exome sequencing and profiling of 
gene expression. 
 


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Protocol ADXS-503-101 
53 
o Evaluate changes in the peripheral T 
cell repertoire by immunosequencing. 
o Characterize subject-specific somatic 
mutations and neoantigens, 
microsatellite instability, tumor 
mutational burden, TCR analysis and 
haplotype. 
4. To characterize changes in circulating free 
DNA (cfDNA) in Part A, Part B, and Part C. 
4. Quantitate changes in cfDNA levels pre- and 
on treatment 
5. 
Investigational Plan 
5.1. 
Study Design 
This is a Phase 1/2, open-label, multi-center study of ADXS-503 administered alone and in 
combination with pembrolizumab in subjects with metastatic squamous or non-squamous NSCLC. 
This study will be performed in 2 phases, a safety phase and an efficacy phase. 
Safety Phase 
In the safety phase, ADXS-503 will be administered as monotherapy in Part A and in combination 
with pembrolizumab in Part B. The subject population for Part A and Part B is as follows: 
• Part A will enroll subjects with metastatic NSCLC who have become refractory or 
intolerant to standard therapy. To be eligible for Part A, subjects must have previously 
received, and then progressed or been intolerant to up to 3 lines of prior therapy in the 
metastatic setting, including approved chemotherapy, targeted therapy, immunotherapy 
and antibody therapy, if eligible. Subjects will be eligible for Part A irrespective of PD-L1 
expression or EGFR or ALK mutation status. However, subjects with an EGFR sensitizing 
mutation or ALK translocation must have received and then progressed or been intolerant 
to at least 1 prior line of approved targeted therapy to be eligible for Part A. 
• Part B will enroll subjects with metastatic NSCLC who meet the following criteria: 
o Are undergoing last treatment with pembrolizumab monotherapy for metastatic 
NSCLC or receiving combination therapy with pembrolizumab + platinum-based 
chemotherapy or pembrolizumab + pemetrexed as maintenance therapy in the 
metastatic setting. 
o The subject’s most recent tumor assessment is consistent with PD according to 
RECIST v1.1 


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Protocol ADXS-503-101 
54 
o There is no evidence of rapid disease progression or clinical deterioration that 
would preclude continuation of pembrolizumab for up to 12 weeks before ADXS-
503 is added-on.  
o Subjects who are receiving pembrolizumab in combination with platinum-based 
chemotherapy or pembrolizumab with pemetrexed as maintenance therapy, will 
continue on pembrolizumab monotherapy every 3 weeks per schedule while other 
drugs are washed-out for 3 weeks. 
o Subject must consent to allow the acquisition of fresh or archival FFPE tumor 
tissue, either a block or unstained slides along with matching blood at baseline, for 
performance of sequencing analysis.  
In Part B, subjects must receive the first dose of ADXS-503 within 12 weeks of the initial 
tumor assessment showing PD (while on treatment with pembrolizumab monotherapy or 
while receiving combination therapy with pembrolizumab + platinum-based chemotherapy 
or pembrolizumab + pemetrexed as maintenance therapy). 
Efficacy Phase 
In the efficacy phase Part B dose-expansion, subjects will be enrolled with metastatic squamous 
or non-squamous NSCLC who meet the same criteria as Part B dose-escalation mentioned above. 
In the efficacy phase (Part C), ADXS-503 will be administered in combination with 
pembrolizumab in subjects who have received no prior systemic treatment in the metastatic setting, 
in accordance with the approved Product Label for pembrolizumab monotherapy for first-line 
treatment. Clinical site must provide documentation of tumor PD-L1 expression and EGFR 
mutation and/or ALK translocation status as evaluated by FDA-approved tests in all patients. 
Baseline tumor samples must express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, 
with no EGFR or ALK genomic tumor aberrations for subjects to be eligible for Part C. Subject 
must consent to allow the acquisition of fresh or archival FFPE tumor tissue, either a block or 
unstained slides along with matching blood at baseline, for performance of sequencing analysis 
(up to first 10 patients enrolled).  


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Protocol ADXS-503-101 
55 
Figure 1 provides a schematic of the study design. Details of the study design are described in 
Section 5.1.1 (safety phase) and Section 5.1.2 (efficacy phase). 
Additional cohorts or study parts may be added to the protocol based on emerging study data or 
the evolving treatment landscape. In this situation, the protocol will be amended accordingly. 
      
           
             
                               
                         
                             
                           
      
                     
              
          
                     
                         
              
          
            
            
 
                                        
 
                                                 
         
 
                                                
                          
 
                                   
                                             
                                             
 
                                        
 
                                                               
                                                      
                                                                  
                                                                    
                                                  
 
                                                                   
                                     
 
                         
               
 
              
 
                           
                           
                   
             
                            
                         
                            
                         
                     
                         
              
                            
                         
                      


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Protocol ADXS-503-101 
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Figure 1 Figure 5. Study Design 
a. 
Escalation to DL2 in Part A will occur in parallel with accrual at DL1 in Part B 
b. 
Upon completion of DL1 in Part B, Dose-expansion of DL1 in Part B will occur in parallel with accrual in Part C. (Accrual in Part B Dose Level 2 may occur upon Sponsor’s decision). Upon 
Investigators’ assessment and decision, treatment schedule with 1x108 CFU of ADXS-503 + 200 mg of pembrolizumab, IV, could shift from every 3 weeks to every 6 weeks after the first year 
of study therapy. 
c. 
If treatment is not safe/tolerable at DL1 in Part A or Part B dose-escalation, a lower dose level (DL -1; 0.5x108 CFU of ADXS-503) will be evaluated before proceeding with Part B and Part C, 
respectively. 
d. 
Upon completion of dose escalation in Part A, ADXS-503 monotherapy may be evaluated in an expansion cohort. 
      
           
             
                               
                         
                             
                           
      
                     
              
          
                     
                         
              
          
            
            
 
                                        
 
                                                 
         
 
                                                
                          
 
                                   
                                             
                                             
 
                                        
 
                                                               
                                                      
                                                                  
                                                                    
                                                  
 
                                                                   
                                     
 
                         
               
 
              
 
                           
                           
                   
             
                            
                         
                            
                         
                     
                         
              
                            
                         
                      


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Protocol ADXS-503-101 
57 
5.1.1. Safety Phase 
Up to approximately 24 subjects with metastatic NSCLC will be enrolled in the safety phase 
(subject population described in Section 5.1 above; see Section 6 for full eligibility criteria). The 
purpose of the safety phase is to evaluate the safety and tolerability of ADXS-503, administered 
as monotherapy and in combination with pembrolizumab, and to determine the MTD or MAD. 
The preliminary clinical and immunological activity of ADXS-503 alone and in combination with 
pembrolizumab, will also be characterized in the safety phase (see Section 4 for study objectives). 
The safety phase will include 2 Parts (Parts A and B dose-escalation). In Part A, ADXS-503 will 
be administered as monotherapy at 2 planned escalating dose levels. In Part B, ADXS-503 will be 
administered at 2 planned escalating dose levels in combination with pembrolizumab. Treatment 
in Part A and Part B will be administered as follows: 
• Part A (ADXS-503 monotherapy dose escalation) 
o Dose level 1 (DL1): 1x108 CFU of ADXS-503 administered every 3 weeks (±2 
days) until disease progression, unacceptable toxicity or another treatment 
discontinuation criterion is met (see Section 8.1). 
o Dose level 2 (DL2): 5x108 CFU of ADXS-503 administered every 3 weeks (±2 
days) until disease progression, unacceptable toxicity or another treatment 
discontinuation criterion is met (see Section 8.1). 
• Part B (ADXS-503 + pembrolizumab dose escalation) 
o Dose level 1 (DL1): 1x108 CFU of ADXS-503 + 200 mg of pembrolizumab 
administered every 3 weeks (±2 days) for up to 2 years or until disease progression, 
unacceptable toxicity or another treatment discontinuation criterion is met (see 
Section 8.1). 
o Dose level 2 (DL2) (To proceed upon Sponsor’s decision): 5x108 CFU of ADXS-
503 + 200 mg of pembrolizumab administered every 3 weeks (±2 days) for up to 2 
years or until disease progression, unacceptable toxicity or another treatment 
discontinuation criterion is met (see Section 8.1).  
Note for Part B:  
▪ The dose of pembrolizumab will be fixed at 200 mg for both dose levels. 
▪ ADXS-503 and pembrolizumab will be administered on the same day, every 3 
weeks (±2 days), starting at Week 1 (±2 days). Upon Investigator assessment 
and discretion, the schedule of therapy with 1x108 CFU of ADXS-503 + 200 
mg of pembrolizumab, IV, could shift from every 3 weeks to every 6 weeks 
after the first year of study treatment. 
See Section 7 for treatment administration instructions. 
 


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Protocol ADXS-503-101 
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Part A (ADXS-503 Monotherapy Dose Escalation) 
In Part A, a 3+3 dose escalation design will be used (rules described below). The first 3 subjects 
enrolled at DL1 will be designated as sentinel subjects and will start treatment at least 14 days 
apart. At DL2 in Part A, only the first 2 subjects will be designated as sentinel subjects and will 
start treatment at least 14 days apart. Dose-limiting toxicity (DLT) will be evaluated over the first 
28 days of treatment for dose escalation purposes in Part A (see Section 9.1.6 for DLT criteria). 
If ADXS-503 is safe and tolerable at DL1 (based on DLT criteria), escalation to DL2 will proceed 
in parallel with accrual at DL1 in Part B (see below for description of Part B). 
If based on DLT criteria, ADXS-503 monotherapy is not safe/tolerable at DL1 in Part A, a lower 
dose level (DL -1; 0.5x108 CFU of ADXS-503) will be evaluated before proceeding with Part B. 
Upon completion of dose escalation in Part A, ADXS-503 monotherapy may be evaluated in an 
expansion cohort. This expansion cohort may be enrolled following consultation and agreement 
between study Investigators and the Sponsor. This expansion cohort may be restricted to the tumor 
type(s) found to be responsive to ADXS-503 monotherapy. The dose of ADXS-503 selected for 
the monotherapy expansion will not exceed the MTD established in Part A. However, the dose 
may be intermediate to those tested in Part A if recommended by the Investigators and the Sponsor. 
Up to approximately 25 subjects will be enrolled in this expansion cohort. 
Part B (ADXS-503 + Pembrolizumab Dose Escalation) 
In Part B, a 3+3 dose escalation design will also be used (rules provided below). As described 
above, accrual at DL1 in Part B will proceed in parallel with escalation to DL2 in Part A (in 
accordance with dose escalation rules). The first 3 subjects enrolled at DL1 in Part B will be 
designated as sentinel subjects and will start treatment at least 14 days apart. At DL2 in Part B, 
only the first 2 subjects will be designated as sentinel subjects and will start treatment at least 14 
days apart. Dose limiting toxicity will be evaluated over the first 28 days of treatment for dose 
escalation purposes in Part B (see Section 9.1.6 for DLT criteria). If ADXS-503 + pembrolizumab 
is safe and tolerable at DL1 in Part B (based on DLT criteria), DL1 will be expanded in parallel 
with accrual will occur in the efficacy phase (Part B-expansion and Part C). Part B-DL2 may occur 
upon Sponsor’s decision. 
If ADXS-503 + pembrolizumab is not safe/tolerable at DL1 in Part B, a lower dose level (DL -1; 
0.5x108 CFU of ADXS-503) will be evaluated before proceeding with Part C. The dose of 
pembrolizumab will remain fixed at 200 mg. 
Note: Available safety data from DL2 in Part A will also be considered for escalation to DL2 in 
Part B. 


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Protocol ADXS-503-101 
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Dose-Escalation Rules for Part A and Part B 
Dose-limiting toxicity will be evaluated over the first 28 days of treatment in Part A and Part B 
(see Section 9.1.6 for DLT criteria). Note: The DLT window will end 7 days after the second 
dose of ADXS-503 monotherapy in Part A and 7 days after the second dose of ADXS-503 and 
pembrolizumab in Part B. If within the 28-day DLT period, a subject does not receive 2 doses 
of ADXS-503 monotherapy in Part A or 2 doses of ADXS-503 and pembrolizumab in Part B, 
the subject may be replaced for DLT assessment purposes. 
Dose escalation in Part A and Part B will proceed as follows: 
• An initial cohort of 3 subjects is enrolled. 
• If 0 of 3 subjects develop DLT, escalation to the next dose level will occur. 
• If 1 of 3 subjects develops DLT: 
o Another 3 subjects will be enrolled at this dose level. 
▪ If 0 of the 3 new subjects develops DLT (for a total of 1/6 subjects with DLT 
at this dose level), escalation to the next dose level will occur. 
▪ If ≥1 of the 3 new subjects develops DLT (for a total of ≥2/6 subjects with DLT 
at this dose level), dose escalation will stop and the dose directly below the 
current dose will be considered the MTD if <2/6 subjects experience DLT at 
this lower dose. 
• If ≥2/3 subjects develop DLT, dose escalation will stop and the dose directly below the 
current dose will be considered the MTD if <2/6 subjects experience a DLT at this lower 
dose level. 
Note: DL -1; 0.5x108 CFU of ADXS-503 will be evaluated if DL1 is not safe and tolerable. 
Prior to declaring the MTD in Part A or Part B, and in consultation with the study Investigators, 
the Sponsor has the option to expand any dose level(s) previously established to be safe, or to 
evaluate intermediate dose levels. In addition, if the MTD is not established, a higher dose level 
may be evaluated with agreement between the Investigators and the Sponsor. Dose escalation rules 
(cohort size, DLT evaluation interval, etc.) will apply to the expanded or additional cohorts. 
No within-subject dose escalation will be permitted in Part A or Part B. If a dose level is found to 
exceed the MTD, subjects enrolled in that dose level may be treated at a lower dose level following 
consultation and agreement between the Investigator and the Sponsor. The dose of pembrolizumab 
in all cases will be fixed at 200 mg. 
 
 


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60 
5.1.2. Efficacy Phase 
Part B Dose Expansion (ADXS-503 + Pembrolizumab) 
• Part B at Dose Level 1 (DL1): 1x108 CFU of ADXS-503 + 200 mg of pembrolizumab 
administered every 3 weeks (±2 days) will be expanded using a Simon’s Two-stage design 
prior to escalating to dose level 2. 
• Upon Investigator assessment and discretion, the schedule of therapy with 1x108 CFU of 
ADXS-503 + 200 mg of pembrolizumab, IV, could shift from every 3 weeks to every 6 
weeks after the first year of study treatment. 
In the Part B expansion cohort (at DL1), up to 43 subjects will be enrolled using a Simon’s Two-
stage design prior to escalating to DL2. In stage I, a total of 18 subjects will be accrued. If there 
are 2 or fewer responses among the 18 subjects, the study will be stopped early. Otherwise, an 
additional 25 subjects will be accrued in stage II, resulting in a total sample size of 43 subjects. 
The purpose of Part B - dose expansion is to gather additional safety, tolerability, efficacy and 
pharmacodynamic information regarding the combination of ADXS-503 and pembrolizumab. The 
population in the dose expansion cohort will be restricted to the same population evaluated in Part 
B. Continuous evaluation of toxicity events in the dose-expansion cohort will be performed 
throughout enrollment. If, at any time, the aggregate rate of treatment-related toxicities meeting 
DLT criteria exceeds 33% across all subjects treated in the dose-expansion cohort, the finding will 
be discussed, and further enrollment may be interrupted. Depending on the nature and grade of 
toxicity and after assessing the risk:benefit ratio, a new lower dose may be initiated following 
consultation and agreement between the Investigators and the Sponsor. 
If stage II completes enrollment of the 43 subjects, and the true response rate is ≥ 0.25, the cohort 
may be expanded up to 140 subjects to further evaluate efficacy, following consultation and 
agreement between the Investigators and the Sponsor. 
 
Part C (ADXS-503 + Pembrolizumab) 
In the efficacy phase (Part C), approximately 25 subjects with metastatic NSCLC who have 
received no prior systemic treatment in the metastatic setting, and whose tumors express PD-L1 
(TPS ≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor 
aberrations, will be enrolled (see Section 6 for full eligibility criteria). Note: Subjects who have 
received adjuvant/neoadjuvant therapy are eligible for Part C if the adjuvant/neoadjuvant therapy 
was completed at least 6 months prior to the diagnosis of metastatic disease. The purpose of Part 


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Protocol ADXS-503-101 
61 
C is to evaluate the safety and preliminary clinical efficacy of ADXS-503 in combination with 
pembrolizumab in this patient population. See Section 4 for study objectives. 
The planned dose of ADXS-503 to be used in combination with pembrolizumab (200 mg) in Part 
C is 1x108 CFU (dose evaluated at DL1 in Part B). This dose may be adjusted but will not exceed 
the MTD established in Part B. ADXS-503 + pembrolizumab will be administered every 3 weeks 
(±2 days) for up to 2 years or until disease progression, unacceptable toxicity or another treatment 
discontinuation criterion is met (see Section 8.1). Upon Investigator assessment and discretion, 
therapy with 1x108 CFU of ADXS-503 + 200 mg of pembrolizumab, IV, could shift from every 3 
weeks to every 6 weeks after the first year of study treatment. 
Note for Part C: . Starting at Week 1, ADXS-503 and pembrolizumab will be administered on the 
same day, every 3 weeks (±2 days), as described above. See Section 7 for treatment administration 
instructions. 
In Part C, toxicities will be evaluated on an ongoing basis. If the aggregate rate of treatment-
related toxicities that meet the DLT criteria (see Section 9.1.6) exceeds 33% at any time (across 
all subjects in Part C), the findings will be discussed between the Sponsor and study 
Investigators, and further enrollment may be interrupted. Depending on the nature and grade of 
the toxicities and after assessing the risk/ benefit, treatment may be adjusted to a lower dose of 
ADXS-503 or an alternative treatment schedule. In all cases, the dose of pembrolizumab will be 
fixed at 200 mg. 
Overall treatment and enrollment stopping rules for this study are described in Section 8.1.2. 
In total in the efficacy phase, up to approximately 165 subjects may be enrolled in Part B. Up to 
43 subjects may be enrolled in Part B expansion of DL1 in the Simon’s Two-stage study cohort 
(S1, n=18 and S2, n= 25) and up to a total of 140 thereafter. As described above, approximately 
up to 25 subjects may be enrolled in Part C. 
5.1.3. Summary of Study Procedures/Assessments 
Refer to the SoA, Section 9, and the sections referenced below for detailed information on study 
procedures and assessments. 
• Subjects will be enrolled in this study according to the Inclusion/ Exclusion criteria 
outlined in Section 6. Clinical site must provide documentation of tumor PD-L1 expression 
and EGFR mutation and/or ALK translocation status as evaluated by FDA-approved tests 
in Part B and Part C patients. Participation in both parts will be dependent upon supplying 
tumor tissue (from fresh biopsy or archival) from a location that has not been radiated. 
Formalin-fixed specimens obtained either at the time of or after the diagnosis of metastatic 
disease will be required for performance of sequencing analysis. In Part C, biopsies 


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62 
obtained PRIOR to receipt of neoadjuvant/adjuvant chemotherapy are NOT permitted. 
Only subjects whose tumors express PD-L1 (TPS ≥1%) as determined by as determined 
by an FDA-approved test, will be eligible for enrollment in Part C. Furthermore, 
documentation of EGFR mutation and/or ALK translocation status will be required for 
subjects with non-squamous NSCLC. If the clinical site is unable to provide this source 
documentation, PD-L1 expression and EGFR/ ALK testing should be performed in all Part 
C patients per institutional standard of care using FDA-approved tests before enrollment.  
See Section 9.5. 
• Study treatment will be administered as described in Section 7. 
• At least 30 minutes prior to each ADXS-503 infusion, all subjects will receive a pre-
infusion prophylactic regimen of adequate hydration, NSAIDs, antihistamines and 
antiemetics to mitigate the potential for “flu-like” symptoms during or after treatment 
infusion. Vital signs will be monitored every 30 minutes (±5 minutes) starting immediately 
prior to each ADXS-503 infusion, until 4 hours after the end of each ADXS-503 infusion. 
To ensure the clearance of Lm, subjects will receive a 7-day course of oral antibiotics 
starting approximately 48 hours after each ADXS-503 infusion. After the final dose of 
ADXS-503, a 3-week course of oral antibiotics will be administered to ensure the clearance 
of Lm. A blood sample will also be collected at 7 days (±3 days) after the completion of 
the 3-week course of oral antibiotics to culture for Lm. See Section 7 and Section 9.2 for 
details. 
• Safety will be assessed throughout this study by AE monitoring, physical examination 
findings, vital sign measurements, monitoring of performance status, and clinical 
laboratory values. Adverse events will be graded in severity according CTCAE v4.03 (see 
Section 9.1). 
• Tumor imaging will be performed by contrast-enhanced CT/MRI as follows: 
o Part A (ADXS-503 monotherapy): Screening (baseline), at Week 8 (±8 days), at 
Week 16 (±7 days), followed by every 9 weeks (±7 days) thereafter, until confirmed 
disease progression or treatment discontinuation, whichever occurs later. 
o Part B (ADXS-503 + pembrolizumab): Screening (baseline), which corresponds to 
the most recent tumor assessment that is consistent with PD (according to RECIST 
v1.1) while on treatment with pembrolizumab monotherapy as last treatment, or 
while receiving combination therapy with pembrolizumab + platinum-based 
chemotherapy or pembrolizumab + pemetrexed as maintenance therapy, as last 
treatment in the metastatic setting. As described above, the first dose of ADXS-503 
will be administered within 12 weeks of the initial assessment of PD. Subsequent 


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Protocol ADXS-503-101 
63 
scans will be performed at Week 8 (±7 days), at Week 16 (± 7 days), and every 9 
weeks (±7 days) thereafter, until confirmed disease progression or treatment 
discontinuation, whichever occurs later. 
o Part C (ADXS-503 + pembrolizumab): Screening (baseline), at Week 8 (±7 days), 
at Week 16 (± 7 days), followed by every 9 weeks (±7 days) thereafter, until 
confirmed disease progression or treatment discontinuation, whichever occurs later. 
See Section 9.4.1 for details on tumor imaging. 
• Tumor response will be evaluated by the Investigator (or designee) according to RECIST 
v1.1 as the basis for the primary analysis of tumor response-based endpoints. Exploratory 
analysis of tumor-response will be performed by the Sponsor (or designee) according to 
iRECIST (see Section 9.4.1 for details). 
o In Part A and Part C, subjects may receive study treatment beyond initial 
Investigator-assessed, RECIST v1.1-defined disease progression, provided the 
criteria in Section 8.1.1 are met. In Part B, all subjects will begin study treatment 
within 12 weeks of initial Investigator-assessed, RECIST v1.1-defined disease 
progression on treatment with pembrolizumab monotherapy as last treatment or 
while receiving combination therapy with pembrolizumab + platinum-based 
chemotherapy or receiving pembrolizumab + pemetrexed as maintenance therapy, 
as last treatment in the metastatic setting (if eligibility criteria are met). 
o In Parts A, B and C, any apparent CR or PR must be confirmed ≥4 weeks after 
radiological imaging indicating CR or PR. 
o Subjects who achieve a confirmed CR may receive up to 2 additional doses of study 
treatment after the date of confirmed CR but must subsequently discontinue 
treatment (see Section 8.1). 
o The following subjects may be eligible for re-treatment upon disease progression, 
with agreement between the Sponsor and Investigator (see Section 8.1): 
▪ Subjects who achieve a confirmed CR during initial study treatment (Parts 
A, B and C) 
▪ Subjects in Part B and Part C who stop trial therapy after 2 years of treatment 
for reasons other than disease progression or intolerability. 
Note: Tumor response data collected during the re-retreatment period will not 
be used for the primary analysis of tumor response endpoints. 


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• In Part A, Part B and Part C, peripheral blood and tumor biopsy samples may be collected 
at baseline and/or during the treatment phase of this study to evaluate biomarkers and 
correlates of immune response. See Section 9.5. 
o Subject must consent to allow the acquisition of fresh or archival FFPE tumor 
tissue, either a block or unstained slides along with matching blood at baseline, 
for performance of sequencing analysis. A fresh tumor biopsy sample must be 
collected within 28 days prior to the first dose of study treatment (baseline) in 
Parts A, B, and C, where feasible, in the opinion of the Investigator. If a fresh 
tumor biopsy sample cannot be obtained, the most recently acquired archived 
tumor biopsy sample may be used for analysis. The archived sample must have 
been biopsied within 3 years of Screening. For archived tumor biopsy samples, 
sufficient tumor samples should be acquired to allow biomarker testing (eg, at 
least unstained 12-15 slides). The baseline tumor biopsy sample (fresh or 
archived) must be from a location that has not been radiated. 
o Blood samples for exploratory immune correlative studies (eg, RNAseq, cfDNA, 
flow cytometry and ELISPOT analysis) may be collected in up to 25 total patients 
from Part B and Part C during Screening, at Week 1  (ie, right before the first 
infusion)  and 7 days (±2 days) after the end of each of the first 3 ADXS-503 
infusions (Weeks 2, 5, and 8) and EOT. Samples for cfDNA are only collected at 
week 1 if samples are not collected during screening. To monitor the durability of 
T cell responses, subsequent blood samples for PBMCs may be taken at Week 25 
(±1 week) and/or at end of treatment 
• Following treatment discontinuation, all subjects will enter a 1-year survival/treatment and 
Lm surveillance (LmS) Follow-up Period (see Section 9.2.1.4 - Management of Listeria 
during Follow-Up).  
o Survival status will be confirmed remotely with the subject, their physician, or their 
legally authorized representative every 3 months (±2 weeks) for up to 1 year. Any 
subsequent anti-cancer treatment received by the subject during this 1-year period 
will also be recorded. 
o During the LmS Follow-up, subjects (or their legally authorized representative) will 
be contacted remotely every 3 months (±2 week) for up to 1 year to determine 
whether they have experienced for several days, the following symptoms that could 
potentially be associated with delayed listeremia and require prompt attention at the 
research site:  
▪ Fever or chills, headache, nausea, confusion or changes in alertness (for 
over 72 hours). 


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5.2. 
Scientific Rationale for Study Design 
Section 3.5 describes the rationale for this study and the selected subject population. 
5.2.1. Rationale for Starting Dose 
The starting dose of ADXS-503 in this study is 1x108 CFU, administered every 3 weeks. This dose 
is selected for three key reasons: (1) the Lm-based construct and attenuated bacterial platform are 
comparable across the entire Advaxis Lm program; (2) clinical data from approximately 540 
subjects treated with Advaxis Lm-based immunotherapies, suggest that a higher dose of 1x109 
CFU is safe and well-tolerated. The AEs observed at 1x109 CFU are primarily associated with 
infusion of the live attenuated Lm vector and are due to innate immune stimulation following 
phagocytosis of the bacteria by APCs. The incidence and severity of infusion-related signs and 
symptoms exhibit a dose-dependent relationship with the total number of CFUs infused (dose 
range of 1x109 to 1x1010 CFU). These AEs have been well managed with a pre-infusion regimen 
of adequate hydration, NSAIDs, antihistamines and antiemetics; (3) however, as described in 
Section 3.4.4.1, 1 subject with NSCLC experienced Grade 3 hypoxia and 1 subject with colorectal 
cancer experienced Grade 3 hypotension and Grade 3 hypoxia following the second dose of the 
neoantigen-based Lm immunotherapy (ADXS-NEO) at 1x109 CFU. Subsequently, 3 subjects 
completed ADXS-NEO therapy at 1×108 CFU dosing level; this dose was well-tolerated for 
subjects with advanced or metastatic solid tumors similarly to what has been observed in this study 
with ADXS-503 at dose level-1 (1x108 CFU). 
Based on these factors, the starting dose of 1x108 CFU of ADXS-503 is considered appropriate. 
This study will use the approved dose of pembrolizumab for the treatment of metastatic NSCLC, 
200 mg every 3 weeks. Refer to the approved pembrolizumab Product Label for additional 
information. 
5.2.2. Rationale for 3+3 Dose Escalation/De-Escalation and Dose-
Expansion Design  
In this study, a standard 3+3 design will be used for dose escalation/de-escalation purposes. The 
3+3 design is a widely used rule-based method for dose escalation/de-escalation in Phase 1 
oncology clinical trials. This approach should allow for a sufficient number of subjects to be 
enrolled at each dose level to evaluate study endpoints, while limiting the number of subjects 
exposed to potential toxicity. 
In Part B dose expansion, a Simon’s Two-stage design will be used. The Simon’s Two-stage design 
is one of the most common multi-stage designs used in Phase 2 oncology clinical trials. The 
Simon’s Two-stage design is an exact design which allows flexibility regarding the null and 
alternative hypotheses, while also allowing stopping for futility (Section 10.1). 


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Protocol ADXS-503-101 
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The rationale for combination of Lm-based immunotherapies in combination with PD-1/PD-L1 
checkpoint inhibitors is described in Section 3.4.2 and Section 3.4.5.1. 
 
5.3. 
Number of Subjects Enrolled 
In the safety phase, up to approximately 24 subjects will be enrolled in either Part A (up to 12 
subjects; ADXS-503 monotherapy; 2 planned dose levels) or Part B (up to 12 subjects; ADXS-503 
+ pembrolizumab; 2 possible dose levels). The actual number of subjects enrolled in Part A and 
Part B will depend upon potential toxicities observed during dose escalation according to the 3+3 
design. 
In the efficacy phase (Part B-dose expansion and Part C combined), up to approximately 165 
subjects may be enrolled. In Part B dose expansion, up to 43 subjects will be enrolled in the 
Simon’s Two-stage study cohort and up to a total of 140 thereafter; and approximately 25 subjects 
will be enrolled in the efficacy phase (Part C; ADXS-503 + pembrolizumab). 
Up to approximately 25 subjects may be enrolled in the Part A expansion cohort. If additional 
cohorts or study parts are added, the protocol will be amended accordingly to reflect the number 
subjects enrolled. 
Subjects may be replaced if they are enrolled in the study but discontinue prior to receiving a dose 
of ADXS-503. Furthermore, if a subject does not receive 2 doses of ADXS-503 monotherapy in 
Part A or 2 doses of ADXS-503 and pembrolizumab in Part B within the 28-day DLT period, the 
subject may be replaced for DLT assessment purposes. 
5.4. 
End of Study Definition 
The planned end of the study is defined as the scheduled date when the survival/treatment 
follow-up period ends for the final subject enrolled in this study. 
6. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. Subjects are eligible for this study only if all 
the following criteria apply: 
6.1. 
Inclusion Criteria 
1. Subject and/or their legally authorized representative must be capable of understanding the 
investigational nature, potential risks, and benefits of the study. The subject and/or their 
legally authorized representative must sign a written informed consent; 


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2. Subject is ≥18 years of age upon signing the Informed Consent Form; 
3. Subject has histologically or cytologically confirmed stage IV (metastatic) squamous or 
non-squamous NSCLC 
o For Parts A and B: 
▪ During Screening, a fresh tumor biopsy must be obtained if clinically 
feasible, in the opinion of the Investigator for biomarker analysis. If a fresh 
biopsy cannot be obtained during Screening, the most recently acquired 
archived tumor biopsy sample may be used for analysis (date of biopsy 
within 3 years of Screening). For archived tumor biopsy samples, sufficient 
tumor samples should be acquired to allow biomarker testing (eg, at least 
unstained12-15 slides). The baseline biopsy must be from a location that 
has not been radiated. 
o Part A only: 
▪ Subject has received, and then progressed or been intolerant to up to 3 lines 
of prior therapy in the metastatic setting, including approved chemotherapy, 
targeted therapy, immunotherapy and antibody therapy, if eligible. Subjects 
who have received >3 lines of prior therapy may be eligible for Part A, upon 
discussion with and approval by the Sponsor. 
• Subjects will be eligible for Part A irrespective of PD-L1 
expression. 
• Subjects will be eligible for Part A irrespective of EGFR or ALK 
mutation status. However, subjects with an EGFR sensitizing 
mutation or ALK translocation must have received and then 
progressed or been intolerant to at least 1 prior line of approved 
targeted therapy to be eligible for Part A. 
Note: Subjects with tumors that harbour neuroendocrine or small cell 
components may be eligible for Part A upon discussion with and 
approval by the Sponsor. 
o Part B only: 
▪ Subject is undergoing treatment with pembrolizumab monotherapy for 
metastatic NSCLC as last therapy 
OR 
▪ Subject is undergoing combination therapy with pembrolizumab + 
platinum-based chemotherapy as the last treatment 
OR 
▪ Subject is receiving pembrolizumab + pemetrexed as maintenance therapy 
after completing treatment with pembrolizumab plus platinum-based 
chemotherapy as the last therapy in the metastatic setting 


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▪ Subject’s most recent tumor assessment is consistent with progressive 
disease (PD) according to RECIST v1.1 
▪ There is no evidence of rapid disease progression or clinical deterioration 
in the subject that would preclude continuation of pembrolizumab treatment 
for up to 12 weeks before ADXS-503 is added-on. 
▪ Subjects who are receiving pembrolizumab in combination with platinum-
based chemotherapy or with pemetrexed, will continue on pembrolizumab 
monotherapy every 3 weeks per schedule while other drugs are washed-
out for 3 weeks 
▪ Subject must consent to allow the acquisition of fresh or archival FFPE 
tumor tissue, either a block or unstained slides along with matching blood 
at baseline, for performance of sequencing analysis. 
Note: In Part B, subjects must receive the first dose of ADXS-503 within 12 weeks 
of the initial tumor assessment showing PD (while on treatment with 
pembrolizumab monotherapy or the below referenced combination therapies with 
pembrolizumab). ADXS-503 will be administered as add-on treatment to the 
ongoing pembrolizumab therapy (whether as monotherapy, or while receiving 
combination therapy with pembrolizumab + platinum-based chemotherapy or 
pembrolizumab + pemetrexed as maintenance therapy, as their last treatment in 
metastatic setting, where subjects have had an initial assessment of PD per RECIST 
v1.1 on the most recent tumor scan).  
o Part C only: 
▪ Subject has received no prior systemic treatment in the metastatic setting. 
Subjects previously treated with adjuvant or neoadjuvant therapy are 
eligible if the adjuvant/neoadjuvant therapy was completed at least 6 
months prior to the diagnosis of metastatic disease.  
▪ Subject must consent to allow the acquisition of fresh or archival FFPE 
tumor tissue, either a block or unstained slides along with matching blood 
at baseline, for performance of sequencing analysis. 
▪ Subject has provided a formalin-fixed tumor sample from a biopsy of a 
tumor lesion either at the time of or after the diagnosis of metastatic disease 
AND from a site not previously irradiated, for correlative work. Biopsies 
obtained PRIOR to the administration of any systemic therapy to treat the 
subject’s tumor (such as neoadjuvant/adjuvant therapy) will not be 
permitted for analysis. The tissue sample must be received by the specialty 
laboratory vendor for tumor testing prior to enrollment. Fine needle 
aspirates, Endobronchial Ultrasound (EBUS) or cell blocks are not 
acceptable. Needle or excisional biopsies, or resected tissue is required. If 
the tumor specimen has not been evaluated for PD-L1 expression, an 
additional tumor specimen must be submitted to the local laboratory facility 
for assessment following an FDA-approved test.  


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▪ Subject’s tumor has PD-L1 expression (TPS≥1%) as determined by an 
FDA-approved test.  
▪ Subject’s tumor has no EGFR or ALK genomic tumor aberrations. EGFR 
sensitizing mutations are mutations that are amenable to treatment with 
TKIs (eg, erlotinib, gefitinib, afatanib, osimertinib). ALK translocations are 
amendable to treatment with TKIs such as crizotinib, alectinib and ceritinib. 
Investigators must produce the source documentation of the EGFR mutation 
and ALK translocation status in all subjects with non-squamous histology 
AND for subjects in whom testing is clinically indicated. If either an EGFR 
sensitizing mutation or ALK translocation is detected, additional 
information regarding the mutation status of the other molecule is not 
required. If the clinical site is unable to provide the source documentation, 
EGFR and ALK testing should be performed per institutional standard of 
care. 
• Subjects with non-squamous histology will not be eligible until the 
EGFR mutation and/or ALK translocation status is known. 
• EGFR and ALK testing will not be required for subjects with 
predominantly squamous histology, as this is not the standard of 
care. 
4. Subject has measurable disease for response assessment as defined by RECIST v1.1 by the 
Investigator; 
5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 
(see Appendix 11); 
6. Subject has a life expectancy of at least 3 months; 
 
7. Subject has recovered to Grade ≤1 by the National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.03 (NCI-CTCAE v4.03) of all clinically significant 
toxic effects of prior anti-cancer chemotherapy, immunotherapy, radiotherapy or surgery 
before entering this study, except for alopecia; 
 
8. Subject has no major existing comorbidities or medical conditions that would preclude 
therapy in the opinion of the Investigator;  
9. Subject has adequate organ function as described in Table 4 below. 


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Table 4: Organ Function Requirements for Study Inclusion 
System 
Laboratory Value 
Hematologic 
Absolute neutrophil count (ANC) a 
≥1 x 109/L (Parts A and B); ≥1.5 x 109/L (Part C) 
Platelets a 
≥75 x 109/L (Parts A and B); ≥100 x 109/L (Part C) 
Hemoglobin a 
≥9 g/dL or ≥5.6 mmol/L 
WBC a 
≥2000/ µL 
Renal 
Serum creatinine OR 
Measured or calculated creatinine clearance 
(CrCl). Note: GFR can also be used in place of 
serum creatinine or CrCl 
≤1.5 x upper limit of normal (ULN) OR 
 
≥50 mL/min for subjects with serum creatinine levels >1.5 
x institutional ULN b 
Hepatic 
Serum total bilirubin 
≤1.5 x ULN (except subjects with Gilbert Syndrome, who 
must have total bilirubin <3 x ULN) 
AST (SGOT) and ALT (SGPT) 
<3 x ULN (Parts A and B); <1.5 x ULN (Part C) 
Endocrine 
Thyroid stimulating hormone (TSH) 
Within normal limits (Parts B and C only). c 
aANC, platelets, hemoglobin, or WBC requirement cannot be met by the use of recent transfusions, or growth factor 
support (G-CSF, erythropoietin, etc.) within 2 weeks prior to treatment initiation.  
bCreatinine clearance should be calculated per institutional standard. 
cIf TSH is not within normal limits, subject may still be eligible if T3 and free T4 are within normal limits.  
 
Contraception 
 
Female subjects 
10. A female subject is eligible to participate if she is not pregnant (see Appendix 5), not 
breastfeeding, and at least one of the following conditions applies: 
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 
OR 
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the 
treatment period and for at least 120 days after the final dose of study treatment; 
11. A female subject of childbearing potential must have a negative urine or serum pregnancy 
test within 72 hours prior to receiving the first dose of study treatment and throughout the 
study as defined in the SoA. If the urine test is positive or cannot be confirmed as negative, 
a serum pregnancy test will be required. 
 
 


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Male subjects 
12. A male subject is eligible if he agrees to follow the contraceptive guidance in Appendix 5 
during the treatment period and for at least 120 days after the final dose of study treatment. 
6.2. 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Subject has an ongoing different primary malignancy. Exceptions include treated basal cell 
carcinoma of the skin or squamous cell carcinoma of the skin; 
2. Subject has an active autoimmune disease requiring systemic treatment within the past 
3 months, a documented history of clinically severe autoimmune disease, or a disorder that 
requires systemic corticosteroids or immunosuppressive agents. Subjects with vitiligo, 
psoriasis, alopecia or resolved childhood asthma/atopy not requiring systemic treatment would 
be an exception to this rule. Subjects with hypothyroidism who are stable on hormone 
replacement (>10 mg daily prednisone equivalent) or Sjögren’s syndrome will not be excluded 
from the study; 
3. Subject has a diagnosis of primary immunodeficiency, is dependent on or has received 
systemic corticosteroid therapy (>10 mg daily prednisone equivalent) or any other form of 
immunosuppressive therapy within 14 days prior to the first dose of study treatment. Inhaled 
or topical corticosteroids, and adrenal replacement corticosteroid doses >10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune disease; 
4. Subject has neuropathy (sensory or motor) ≥Grade 3 per CTCAE v4.03; 
5. Subject has had an allogeneic tissue/solid organ transplant; 
 
6. Subject has known history (past 5 years) or any evidence of interstitial lung disease (ILD) 
OR active, non-infectious pneumonitis that has required oral or IV steroids; 
7. Subject has untreated central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided they 
are stable (no new or enlarging brain metastases) by imaging for at least 2 weeks following 
treatment, and clinically stable with no symptoms due to CNS metastasis, and are not using 
corticosteroids for at least 14 days prior to the start of study treatment; 
8. Subject has a concurrent unstable or uncontrolled medical condition (eg, active uncontrolled 
systemic infection, unstable angina, congestive heart failure, uncontrolled diabetes) or other 
chronic disease, which in the opinion of the Investigator could compromise the subject or the 
study; 


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Protocol ADXS-503-101 
72 
9. Subject has a known history of human immunodeficiency virus (HIV) infection (HIV 1/2 
antibodies); 
10. Subject has a known active hepatitis B (eg, HBsAg reactive) or hepatitis C infection (eg, HCV 
RNA [qualitative] is detected) or tuberculosis; 
11. Subject has an active infection requiring systemic therapy or is dependent on or currently 
receiving antibiotics that cannot be discontinued before dosing. (Note: Subjects who 
discontinue an antibiotic prior to dosing must wait at least 5 half-lives after the last dose of 
antibiotic before receiving any study treatment); 
12. Subject has known psychiatric or substance abuse disorder(s) that would interfere with 
cooperation with the requirements of the study; 
13. Subject has an implanted medical device that poses a high risk for bacterial colonization and/or 
that cannot be easily removed (eg, prosthetic joints, artificial heart valves, pacemakers, 
orthopedic screws, bone grafts, or other critical exogenous implants). NOTE: More common 
devices and prosthetics that include arterial and venous stents, hernia mesh, some metal plates, 
dental and breast implants and venous access devices (eg, Port-a-Cath or Mediport) are 
permitted. Sponsor must be contacted prior to consenting any subject who has any other device 
or implant; 
14. Subject is pregnant or breastfeeding, or plans to become pregnant or to father children, from 
the Screening visit through at least 120 days after the final dose of study treatment; 
15. Subject has a contraindication (eg, sensitivity/allergy) to trimethoprim/ sulfamethoxazole, 
ampicillin, and another antibiotic to which Lm is typically sensitive (eg, erythromycin, 
fluoroquinolones – see Section 9.2.1.3.1.1for further details); 
16. Subject has a contraindication to non-steroidal anti-inflammatory drugs (NSAIDs); 
a. Subject has a known allergy to any component of the study formulation(s); 
17. Subject has a history of listeriosis;  
18. Subject has any other serious or uncontrolled physical or mental condition/disease that, as 
judged by the Investigator, could place the subject at higher risk derived from their 
participation in the study, could confound results of the study, or would be likely to prevent 
compliance with the requirements of the study; 
Prior/Concomitant Therapy 
19. Subject has received chemotherapy and/or radiation therapy (except palliative radiation 
therapy for disease-related pain) within 2 weeks of the first dose of study treatment; 
20. Subject has received monoclonal antibody or other biologic therapy within 5 half-lives or 28 
days prior to the first dose of study treatment, whichever is shorter. An exception to this 
exclusion criterion will be pembrolizumab monotherapy for subjects enrolled in Part B; 


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Protocol ADXS-503-101 
73 
21. Subject has received prior treatment with an Lm-based immunotherapy; 
a. Subject is receiving or plans to receive future treatment with PI3K or TNFα inhibitors; 
b. Subject has received a live vaccine within 30 days prior to the first dose of study treatment; 
c. Subject has not recovered to baseline from AEs, with the exception of alopecia, due to 
previously administered agent(s); 
22. Subject has had major surgery within 6 weeks prior to the initiation of study treatment.  NOTE: 
All surgical complications must have recovered to baseline or Grade ≤1 prior to the initiation 
of study therapy. Sponsor must be consulted prior to enrolling subjects on the study who 
recently had a major surgery or have a new artificial implant, and/or devices; 
Prior/Concurrent Clinical Study Experience 
23. Subject is currently participating in or has participated in a study of an investigational agent(s) 
within 4 weeks of the first dose of study treatment; 
24. Subject is or has an immediate family member (spouse or children) who, as investigational site 
or sponsor staff, is directly involved with this trial, unless prospective IRB approval (by chair 
or designee) is given allowing exception to this criterion for a specific subject; 
Exclusion Criteria for Part C only 
25. In Part C, subject has received systemic therapy for the treatment of their metastatic NSCLC. 
Completion of treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant 
therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of 
metastatic disease; 
26. In Part C, subject has an EGFR sensitizing mutation and/or an ALK translocation; 
27. In Part C, baseline tumor specimen is not evaluable for PD-L1 expression. If an additional 
tumor specimen is submitted AND evaluable for PD-L1 expression, the subject will be eligible 
to participate if the tumor expresses PD-L1 (TPS ≥1%) as determined by an FDA-approved 
test with no EGFR or ALK genomic tumor aberrations; 
28. In Part C, subject has received prior systemic chemotherapy, biological therapy, OR major 
surgery within 6 weeks of the first dose of study treatment; received thoracic radiation therapy 
of >30 Gy within 6 months of first dose of study treatment; 
29. In Part C, subject has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CD137, or anti-CTLA-4 antibody, or any other antibody or drug that specifically targets T cell 
co-stimulation or immune checkpoint pathways.  


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Protocol ADXS-503-101 
74 
6.3. 
Lifestyle Restriction 
No lifestyle restrictions are specified in this protocol. Subjects should maintain a normal diet 
unless modifications are required to manage an AE such as nausea, diarrhea or vomiting. 
6.4. 
Screen Failures 
Screen failures are defined as subjects who consent to undergo Screening for the clinical study but 
fail to meet the required entry criteria. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse event (SAE). 
A subject who has laboratory test results, vital signs, or other findings that do not satisfy the 
eligibility criteria may have the test(s) repeated. These tests may be repeated as soon as the 
Investigator believes the re-test result to likely be within the acceptable range to satisfy the entry 
criteria but must be completed within the Screening period. The subject will not be required to 
sign another ICF, and the original subject identification number will be used. If the laboratory 
test(s) cannot be performed within the Screening period, if the re-test(s) does not meet the entry 
criteria or if the subject’s medical condition has changed significantly during the Screening period 
so that inclusion/exclusion criteria are no longer met, then the subject is considered a Screen 
failure. 
Individuals who do not meet the criteria for participation in this study (Screen failure) may be re-
screened after consultation with the Sponsor and will require a new subject identification number. 
Part C: If the tumor specimen has not been evaluated for PD-L1 expression, it may be tested at a 
local laboratory facility, so the subject can be eligible to participate if the tumor expresses PD-L1 
(TPS ≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor 
aberrations. 
7. 
Treatments 
The rationale for the starting dose of ADXS-503 (1x108 CFU) is described in Section 5.2.1.  This 
study will use the approved dose of pembrolizumab for treating patients with metastatic NSCLC: 
200 mg every 3 weeks. Upon Investigator assessment and discretion, the schedule of therapy with 
ADXS-503 plus 200 mg of pembrolizumab, IV, could shift from every 3 weeks to every 6 weeks 
after the first year of study treatment. Refer to the approved pembrolizumab Product Label for 
additional information. 


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Protocol ADXS-503-101 
75 
7.1. 
Treatments Administered 
7.1.1. ADXS-503 Monotherapy (Part A) 
In Part A, ADXS-503 will be administered as monotherapy at 2 planned escalating dose levels 
(1x108 CFU and 5x108 CFU). If treatment with ADXS-503 monotherapy at the starting dose of 
1x108 CFU (DL1) is not safe and tolerable (based on DLT criteria), a lower dose of 0.5x108 CFU 
(DL -1) will be evaluated. Treatment in Part A will be administered as outlined in Table 5 and as 
described below.  
Table 5: Treatment in Part A: ADXS-503 Monotherapy 
Treatment 
Dose Level 
(DL) 
Dose 
 
Dose 
Frequency 
Route of 
Administration 
 
 
ADXS-503  
2 
5x108 CFU 
Q 3 weeks 
Intravenous 
1 
(starting dose) 
1x108 CFU 
Q 3 weeks 
Intravenous 
-1 
0.5x108 CFU 
Q 3 weeks 
Intravenous 
 
In Part A, each subject will receive ADXS-503 monotherapy at their enrolled dose level, every 3 
weeks (±2 days) until disease progression, unacceptable toxicity or another treatment 
discontinuation criterion is met (see Section 8.1). Treatment with ADXS-503 must occur within 3 
days of the scheduled infusion day unless a delay in dosing is required to allow for the resolution 
of AEs as outlined in Section 7.6. The interval between each subsequent dose of ADXS-503 should 
not be less than 2 weeks without Sponsor approval. The following pre-infusion, infusion and post-
infusion procedures are required for each ADXS-503 treatment infusion. 
Pre-infusion: A pre-infusion regimen of adequate hydration, NSAIDs, antihistamines and 
antiemetics as a prophylaxis for “flu-like” symptoms will be completed at least 30 minutes prior 
to each ADXS-503 infusion (see Section 9.2.1.1). Vital signs will be monitored every 30 minutes 
(±5 minutes) starting immediately prior to each ADXS-503 infusion, until 4 hours after the end of 
each ADXS-503 infusion (see Section 9.2.1.2). 
Infusion: Administer ADXS-503 as a single IV infusion over 60 (±10) minutes through a 
dedicated infusion line. ADXS-503 must not be administered as an IV push or bolus injection. 
ADXS-503 must not be administered via an existing or newly placed central venous catheter or 
infusion port that is planned to be used for another purpose. In addition, the central venous catheter 
or infusion port must not be used for 72 hours following the completion of the ADXS-503 infusion 


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Protocol ADXS-503-101 
76 
until after the subject’s first post-infusion dose of oral antibiotics is administered. Refer to the 
Pharmacy Manual for treatment preparation and additional treatment administration instructions. 
Vital signs will continue to be monitored every 30 minutes (±5 minutes) during each ADXS-503 
infusion. 
Post-infusion:  Following each infusion of ADXS-503, vital signs will continue to be monitored 
every 30 minutes (±5 minutes) for 4 hours and a 7-day oral antibiotic regimen will be dispensed. 
The first antibiotic dose will be administered at approximately 48 hours after the completion of 
each ADXS-503 infusion. See Section 9.2.1.3 for additional information. 
Refer to the Pharmacy Manual for treatment preparation and detailed treatment administration 
instructions. 
Refer to Section 9.2.2 for supportive care guidelines for ADXS-503 treatment. Guidelines for the 
management of infusion reactions can be found in Appendix 6. Guidelines for the management of 
other acute events, including hypotension, hypoxia, encephalopathy, organ toxicity, fever and 
constitutional symptoms can be found in Appendix 7. 
7.1.2. ADXS-503 + Pembrolizumab (Part B Dose-Escalation and Dose-
Expansion) 
In Part B dose escalation, ADXS-503 will be administered at 2 planned escalating dose levels 
(1x108 CFU and 5x108 CFU) in combination with a fixed dose of pembrolizumab (200 mg). If 
treatment with ADXS-503 + pembrolizumab is not safe and tolerable at the starting dose of 1x108 
CFU (DL1) (based on DLT criteria), a lower dose of 0.5x108 CFU (DL -1) will be evaluated. 
Treatment in Part B dose expansion, ADXS-503 will be administered at DL1 (1x108 CFU) in 
combination with a fixed dose of pembrolizumab (200 mg) as outlined in Table 6 and as described 
below. 


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Protocol ADXS-503-101 
77 
Table 6: Treatment in Part B: ADXS-503 + Pembrolizumab 
Treatment 
Dose Level 
(DL) 
Dose 
 
Dose 
Frequency a 
Route of 
Administration 
 
 
ADXS-503  
2  
5x108 CFU 
Q 3 weeks 
Intravenous 
1  
(starting/expansion 
dose) 
1x108 CFU 
Q 3 weeks 
Intravenous 
-1  
0.5x108 CFU Q 3 weeks 
Intravenous 
PLUS 
Pembrolizumab  
N/A 
200 mg 
Q 3 weeks 
Intravenous 
a: At each dose level in Part B, ADXS-503 and pembrolizumab will be administered on the same day, every 3 
weeks, starting at Week 1 (±2 days). 
 
In Part B, each subject will receive ADXS-503 at their enrolled dose level in combination with 
200 mg of pembrolizumab, every 3 weeks (±2 days) until disease progression, unacceptable 
toxicity, the completion of 2 years of study treatment or another treatment discontinuation criterion 
is met (see Section 8.1). Upon Investigator assessment and discretion, the schedule of therapy with 
ADXS-503 + 200 mg of pembrolizumab, IV, could shift from every 3 weeks to every 6 weeks 
after the first year of study treatment. Treatment with ADXS-503 and pembrolizumab will start at 
Week 1 (±2 days). Treatment with ADXS-503 and pembrolizumab must occur within 3 days of 
the scheduled infusion day unless a delay in dosing is required to allow for the resolution of AEs 
as outlined in Section 7.6. The interval between each subsequent dose of ADXS-503 and each 
subsequent dose of pembrolizumab should not be less than 2 weeks without Sponsor approval. 
Week 1 (±2 days) onwards: On each treatment day, pembrolizumab will be infused first over 30 
(±5) minutes, followed approximately 60 (±15) minutes after the end of the pembrolizumab 
infusion by the ADXS-503 infusion. Treatment will be administered as follows: 
1. Pembrolizumab Infusion: Administer pembrolizumab as a single IV infusion over 30 (±5) 
minutes through a dedicated infusion line containing a sterile, non-pyrogenic, low-protein binding 
0.2 micron to 5 micron in-line or add-on filter. Pembrolizumab must not be administered as an IV 
push or bolus injection. Pembrolizumab must not be administered via an existing or newly placed 
central venous catheter or infusion port that is planned to be used for another purpose. A separate 
infusion line will be used to administer ADXS-503. For enrolled patients with difficulty to access 
veins, one infusion line for pembrolizumab may be used to administer ADXS-503 provided it is 
flushed after the pembrolizumab infusion, at pre-infusion and post-infusion of ADXS-503 
regimen. If the infusion line is the same, the in-line filter used for the infusion of pembrolizumab 


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Protocol ADXS-503-101 
78 
must be removed before infusing ADXS-503. See the approved pembrolizumab Product Label and 
Pharmacy Manual for treatment preparation and detailed treatment administration instructions. 
2. ADXS-503 Infusion: Following the administration of pembrolizumab and before the 
administration of ADXS-503, the Investigator must confirm that the subject is in a stable medical 
condition and any ongoing AEs, if present, would not preclude the administration of ADXS-503. 
If ongoing AEs do preclude the administration of ADXS-503, ADXS-503 treatment must be 
delayed until the resolution of the AEs. 
The following pre-infusion, infusion and post-infusion procedures are required for each ADXS-
503 treatment infusion. 
Pre-infusion: A pre-infusion regimen of adequate hydration, NSAIDs, antihistamines and 
antiemetics as a prophylaxis for “flu-like” symptoms will be completed at least 30 minutes prior 
to each ADXS-503 infusion (see Section 9.2.1.1). Vital signs will be monitored every 30 minutes 
(±5 minutes) starting immediately prior to each ADXS-503 infusion, until 4 hours after the end of 
each ADXS-503 infusion (see Section 9.2.1.2). 
Infusion: Administer ADXS-503 as a single IV infusion over 60 (±10) minutes through a 
dedicated infusion line, or through the same one used for pembrolizumab administration, if needed 
for subjects with vein access difficulties. Where one infusion line is used for the administration of 
both drugs, it must be flushed after each infusion, ie, after the pembrolizumab infusion and pre- 
and post-infusion of ADXS-503 infusion regimen (Section 7.1.1.). In addition, if the infusion line 
is the same, the in-line filter used for the infusion of pembrolizumab must be removed before 
infusing ADXS-503. ADXS-503 must not be administered as an IV push or bolus injection. 
ADXS-503 must not be administered via an existing or newly placed central venous catheter or 
infusion port that is planned to be used for another purpose. On the other hand, an existing central 
venous catheter or infusion port may be used to withdraw blood samples for correlative analysis 
in this trial. Refer to the Pharmacy Manual for treatment preparation and detailed treatment 
administration instructions. 
Vital signs will continue to be monitored every 30 minutes (±5 minutes) during each ADXS-503 
infusion. 
Post-infusion:  Following each infusion of ADXS-503, vital signs will continue to be monitored 
every 30 minutes (±5 minutes) for 4 hours and a 7-day oral antibiotic regimen will be dispensed. 
The first antibiotic dose will be administered at approximately 48 hours after the completion of 
each ADXS-503 infusion. See Section 9.2.1.3 for additional information. 


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Protocol ADXS-503-101 
79 
Refer to Section 9.2.2 for clinical safety management and supportive care guidelines for ADXS-
503 and pembrolizumab treatment. Guidelines for the management of infusion reactions can be 
found in Appendix 6. Guidelines for the management of other acute events, including hypotension, 
hypoxia, encephalopathy, organ toxicity, fever and constitutional symptoms can be found in 
Appendix 7. 
Note: If any toxicity results in the discontinuation of either ADXS-503 or pembrolizumab but not 
both, treatment with the non-discontinued study drug may continue as monotherapy in Part B, 
unless the nature of the toxicity precludes administration of any treatment (see Section 7.6). In 
such cases, the treatment administration instructions for the individual study drug 
administered as monotherapy are to be followed until treatment discontinuation. 
7.1.3. ADXS-503 + Pembrolizumab (Part C) 
In Part C, ADXS-503 will be administered at a planned dose of 1x108 CFU in combination with a 
fixed dose of pembrolizumab (200 mg). Treatment in Part C will be administered as outlined in 
Table 7, and as described below. 
Table 7: Treatment in Part C: ADXS-503 + Pembrolizumab 
Treatment 
Dose 
 
Dose 
Frequency a 
Route of 
Administration 
ADXS-503  
1x108 CFU 
Q 3 weeks 
Intravenous 
PLUS 
Pembrolizumab 
200 mg 
Q 3 weeks 
Intravenous 
a: In Part C, ADXS-503 and Pembrolizumab will be administered on the same day, every 3 weeks starting on Week 
1 (±2 days). However, after first year of treatment, the dosing schedule could be changed to every 6 weeks, upon 
investigator assessment and discretion. 
In Part C, starting at Week 1 (±2 days), ADXS-503 and pembrolizumab will be administered on 
the same day, every 3 weeks (±2 days) until disease progression, unacceptable toxicity, the 
completion of 2 years of study treatment, or another treatment discontinuation criterion is met (see 
Section 8.1). Upon Investigator assessment and discretion, the schedule of therapy with ADXS-
503 + 200 mg of pembrolizumab, IV, could shift from every 3 weeks to every 6 weeks after the 
first year of study treatment. Treatment with ADXS-503 and pembrolizumab must occur within 3 
days of the scheduled infusion day unless a delay in dosing is required to allow for the resolution 
of AEs as outlined in Section 7.6. The interval between each subsequent dose of ADXS-503 and 
each subsequent dose of pembrolizumab should not be less than 2 weeks without Sponsor 
approval. 


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Protocol ADXS-503-101 
80 
Follow the treatment administration instructions outlined below for each respective agent. 
1. Pembrolizumab Infusion: Administer pembrolizumab as a single IV infusion over 30 (±5) 
minutes through a dedicated infusion line containing a sterile, non-pyrogenic, low-protein binding 
0.2 micron to 5 micron in-line or add-on filter. Pembrolizumab must not be administered as an IV 
push or bolus injection. Pembrolizumab must not be administered via an existing or newly placed 
central venous catheter or infusion port that is planned to be used for another purpose. The same 
infusion line may be used to administer ADXS-503. For example, enrolled patients who present 
with difficulty to accessing their vein, could use one infusion line to administer both drugs if it is 
flushed after the pembrolizumab infusion and pre- and post-ADXS-503 infusion regimen (Section 
7.1.1.). If the infusion line is the same, the in-line filter used for the infusion of pembrolizumab 
must be removed before infusing ADXS-503. See the approved pembrolizumab Product Label 
and Pharmacy Manual for treatment preparation and detailed treatment administration 
instructions. 
2. ADXS-503 Infusion: Following the administration of pembrolizumab and before the 
administration of ADXS-503, the Investigator must confirm that the subject is in a stable medical 
condition and any ongoing AEs, if present, would not preclude the administration of ADXS-503. 
If ongoing AEs do preclude the administration of ADXS-503, ADXS-503 treatment must be 
delayed until the resolution of the AEs. 
The following pre-infusion, infusion and post-infusion procedures are required for each ADXS-
503 treatment infusion. 
Pre-infusion: A pre-infusion regimen of adequate hydration, NSAIDs, antihistamines and 
antiemetics as a prophylaxis for “flu-like” symptoms will be completed at least 30 minutes prior 
to each ADXS-503 infusion (see Section 9.2.1.1). Vital signs will be monitored every 30 minutes 
(±5 minutes) starting immediately prior to each ADXS-503 infusion, until 4 hours after the end of 
each ADXS-503 infusion (see Section 9.2.1.2). 
Infusion: Administer ADXS-503 as a single IV infusion over 60 (±10) minutes through a 
dedicated infusion line or through the same one used for pembrolizumab administration, if needed 
for subjects with vein access difficulties. Where one infusion line is used to administer both drugs, 
it must be flushed after each infusion, ie, after the pembrolizumab infusion, pre- and post-infusion 
of ADXS-503 regimen (Section 7.1.1). In addition, if the infusion line is the same, the filter used 
for the infusion of pembrolizumab must be removed before infusing ADXS-503. ADXS-503 must 
not be administered as an IV push or bolus injection. ADXS-503 must not be administered via an 
existing or newly placed central venous catheter or infusion port that is planned to be used for 
another purpose. The central venous catheter or infusion port may be used to withdraw blood 


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Protocol ADXS-503-101 
81 
samples for correlative analysis. Refer to the Pharmacy Manual for treatment preparation and 
detailed treatment administration instructions. 
Vital signs will continue to be monitored every 30 minutes (±5 minutes) during each ADXS-503 
infusion. 
Post-infusion:  Following each infusion of ADXS-503, vital signs will continue to be monitored 
every 30 minutes (±5 minutes) for 4 hours and a 7-day oral antibiotic regimen will be dispensed. 
The first antibiotic dose will be administered at approximately 48 hours after the completion of 
each ADXS-503 infusion. See Section 9.2.1.3 for additional information. 
Refer to Section 9.2.2 for clinical safety management and supportive care guidelines for ADXS-
503 and pembrolizumab treatment. Guidelines for the management of infusion reactions can be 
found in Appendix 6. Guidelines for the management of other acute events, including hypotension, 
hypoxia, encephalopathy, organ toxicity, fever and constitutional symptoms can be found in 
Appendix 7. 
Note: If any toxicity results in the discontinuation of either ADXS-503 or pembrolizumab but not 
both, treatment with the non-discontinued study drug may continue as monotherapy in Part C, 
unless the nature of the toxicity precludes administration of any treatment (see Section 7.6). In 
such cases, the treatment administration instructions for the individual study drug 
administered as monotherapy are to be followed until treatment discontinuation. 
7.2. 
Preparation/ Handling/ Storage/ Accountability 
1. ADXS-503 is shipped at minus (-)80C with a temperature monitor included in the box 
that will be retrieved by the courier. It is imperative that all ADXS-503 drug shipments be 
stored at minus (-)80C (±10C) immediately after being removed from the shipping 
container. Recommended safety measures for preparation and handling of ADXS-503 
include laboratory coats and gloves. 
2. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment. 
3. Only subjects enrolled in the study may receive study treatment and only authorized site 
staff may administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with 
the labeled storage conditions with access limited to the Investigator and authorized site 
staff. 
4. Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site or by a third party outside of the site, 
per institutional policy. It is the Investigator's responsibility to arrange for disposal of all 


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Protocol ADXS-503-101 
82 
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. 
5. Further guidance is provided in the Pharmacy Manual. 
ADXS-503 will be supplied by the Sponsor. Pembrolizumab may be provided by the Sponsor 
or locally by the trial site, subsidiary or designee, depending on local country operational or 
regulatory requirements. For any commercially available product (including pembrolizumab) 
that is provided by the trial site, subsidiary or designee, every attempt will be made to source 
these supplies from a single lot/batch number. The trial site will be responsible for recording the 
lot number, manufacturer and expiry date of any locally purchased 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 trial 
treatments in accordance with the protocol and any applicable laws and regulations. 
7.3. 
Treatment Compliance 
Treatment compliance is not applicable to this study because ADXS-503 and pembrolizumab will 
be administered by the Investigator or designee in a clinical setting. 
7.4. 
Method of Treatment Assignment 
Each subject who has signed Informed Consent and has been screened for entry into the study, 
will be assigned a unique, sequential number that also includes the subject’s study site. 
In Part A, ADXS-503 will be administered as monotherapy at 2 planned escalating dose levels. In 
Part B, ADXS-503 will be administered at 2 planned escalating dose levels in combination with a 
fixed dose of pembrolizumab (200 mg). The dose of ADXS-503 administered to each subject will 
depend on the point at which the subject enrolls in the study during the dose escalation phase for 
Part A and Part B. 
In Part C, all subjects will receive ADXS-503 + pembrolizumab. The planned dose of ADXS-503 
in Part C is 1x108 CFU in combination with a fixed dose of pembrolizumab (200 mg). 
See Section 5.1 for a description of the study design. 
7.5. 
Blinding 
This is an open-label study. Therefore, the Sponsor, Investigator and subject will be aware of the 
treatment and dose administered. 


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Protocol ADXS-503-101 
83 
7.6. 
Treatment Modification and Discontinuation Guidelines for Toxicity 
Treatment will be delayed, or treatment will be discontinued due to specific toxicities as outlined 
in Section 7.6.1 for ADXS-503 and Section 7.6.2 for pembrolizumab. 
For subjects treated with ADXS-503 in combination with pembrolizumab (Part B and Part C), the 
following guidance should be followed: 
• Treatment modifications and treatment discontinuation as a result of toxicity should be 
based on the causal agent. Toxicity that was assessed as being caused by ADXS-503 should 
be managed according to the criteria for dose delays and treatment discontinuation for 
ADXS-503 (see Section 7.6.1), whereas toxicity that was assessed as being caused by 
pembrolizumab should be managed according to the criteria for dose delays and treatment 
discontinuation for pembrolizumab (see Section 7.6.2). This means that when 
administration of one agent has been delayed for toxicity, the other agent may be 
administered as scheduled, unless the nature of the toxicity precludes administration of any 
treatment. Similarly, treatment with either ADXS-503 or pembrolizumab may be 
discontinued when either drug is considered to be the cause of the toxicity. 
• If any toxicity results in the discontinuation of either ADXS-503 or pembrolizumab but not 
both, treatment with the non-discontinued study drug may continue as monotherapy, unless 
the nature of the toxicity precludes administration of any treatment. 
• On the day of dosing (from Week 1 [± 2 days] onwards in Part B and Part C), following 
the administration of pembrolizumab and before the administration of ADXS-503, the 
Investigator must confirm that the subject is in a stable medical condition and any ongoing 
AEs, if present, would not preclude the administration of ADXS-503. If ongoing AEs do 
preclude the administration of ADXS-503, ADXS-503 treatment must be delayed until the 
resolution of the AEs. 
 
7.6.1. ADXS-503: Treatment Modification and Discontinuation 
Guidelines 
Treatment modification and discontinuation guidelines for ADXS-503-related toxicities are 
outlined in Table 8 below. 


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Protocol ADXS-503-101 
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Table 8: Treatment Modifications/Discontinuation for ADXS-503-Related Toxicity 
Toxicity 
Grade 
Interrupt or Hold 
Treatment? 
Timing for Restarting 
Treatment 
Discontinue 
Treatment 
Hematologic 
1, 2, 3 
No  
N/A 
N/A 
4 
Yes 
Toxicity resolves to 
Grade ≤ 1 or baseline 
within 12 weeks of 
previous dose of 
ADXS-503 
Toxicity does not 
resolve to Grade ≤ 1 
or baseline within 12 
weeks of previous 
dose of ADXS-503 
Non-
hematologic 
(excluding 
AEs 
described in 
footnote b) b 
1 
No 
N/A 
N/A 
2-3 
Yes 
Toxicity resolves to 
Grade ≤ 1 or baseline 
within 12 weeks of 
previous dose of 
ADXS-503 a 
Toxicity does not 
resolve to Grade ≤ 1 
or baseline within 12 
weeks of previous 
dose of ADXS-503 a 
4 
N/A 
Permanently 
discontinue treatment 
Permanently 
discontinue treatment 
a With Investigator and Sponsor agreement, subjects with a non-hematologic AE (eg, alopecia, vitiligo) still at Grade 2 after 12 
weeks, may continue treatment only if asymptomatic and controlled. 
b Refer to Appendix 6 for recommended management guidelines for AEs associated with infusion reactions; Appendix 7 for 
recommended management guidelines for other acute events, including hypotension, hypoxia, encephalopathy, organ toxicity, 
fever and constitutional symptoms; and Appendix 8 for guidelines to manage immune-related AEs.  
Treatment with ADXS-503 must occur within 3 days of the scheduled infusion day (every 3 weeks 
±2 days) unless a delay in dosing is required to allow for the resolution of AEs (see Table 8 above). 
Subjects who require a delay of ADXS-503 dosing should be re-evaluated weekly or more 
frequently if clinically indicated and resume ADXS-503 dosing when re-treatment criteria are met 
as outlined in Table 8 above. If treatment with ADXS-503 is delayed by >12 weeks from the 
previous dose of ADXS-503 for toxicities as outlined in Table 8, treatment should be discontinued 
after consultation with the Sponsor. 
Dosing delays lasting >12 weeks from the previous dose of ADXS-503 that occur for non-drug-
related reasons may be allowed if approved by the Medical Monitor. Prior to re-initiating 
treatment, the Medical Monitor must be consulted. Periodic study visits to assess safety should 
also continue every 6 weeks or more frequently if clinically indicated during dosing delays lasting 
>12 weeks. 
If a subject discontinues treatment at their enrolled dose level due to toxicity, but is otherwise 
experiencing clinical benefit, he/she may be eligible to receive ADXS-503 at a lower dose level. 
This dose reduction may only take place upon discussion and agreement between the Investigator 
and the Sponsor, and once toxicities have returned to baseline or resolved. Only one dose reduction 
for ADXS-503 is allowed per subject. No other reason for dose reduction will be considered. All 
study-related procedures will apply for subsequent doses at the reduced dose. 


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7.6.2. Pembrolizumab: Treatment Modification and Discontinuation 
Guidelines 
Treatment modification and discontinuation guidelines for pembrolizumab-related toxicities are 
outlined in Table 9 below. 
Table 9: Treatment Modifications/ Discontinuation for Pembrolizumab-Related Toxicity 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Subject d 
Diarrhea/Colitis 
2-3 
Toxicity resolves to Grade 
0-1. 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks. 
4 
Permanently discontinue. 
Permanently discontinue. 
Hypophysitis 
2-4 
Toxicity resolves to Grade 
0-1.  Therapy with 
pembrolizumab can be 
continued while hormone 
replacement therapy is 
instituted. 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks. 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 
0-1. 
Toxicity does not resolve within 12 weeks 
of last dose. 
3-4 
Permanently discontinue 
(see exception below). a 
Permanently discontinue. 
Type 1 diabetes 
mellitus (T1DM) 
(if new onset) or 
Hyperglycemia 
T1DM or   
3-4 
Hold pembrolizumab for 
new onset Type 1 diabetes 
mellitus or Grade 3-4 
hyperglycemia associated 
with evidence of beta cell 
failure. 
Resume pembrolizumab when subjects are 
clinically and metabolically stable. 
Hyperthyroidism  
3 
Toxicity resolves to Grade 
0-1. 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks. 
4 
Permanently discontinue. 
Permanently discontinue. 
Hypothyroidism 
1-4 
Therapy with 
pembrolizumab can be 
continued while thyroid 
replacement therapy is 
instituted. 
Therapy with pembrolizumab can be 
continued while thyroid replacement therapy 
is instituted. 
Infusion Reaction 
2 b 
Toxicity resolves to Grade 
0-1. 
Permanently discontinue if toxicity develops 
despite adequate premedication. 
3-4  
Permanently discontinue. 
Permanently discontinue. 


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Subject d 
Pneumonitis 
2 
Toxicity resolves to Grade 
0-1. 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks. 
3-4 or 
Recurrent 2 
Permanently discontinue. 
Permanently discontinue. 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 
0-1. 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks. 
3-4 
Permanently discontinue. 
Permanently discontinue. 
All Other Drug-
Related Toxicity c 
3 or Severe 
Toxicity resolves to Grade 
0-1. 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks. 
4 
Permanently discontinue. 
Permanently discontinue. 
Note: Permanently discontinue for any severe or Grade 3 (Grade 2 for pneumonitis) drug-related AE that recurs 
or any life-threatening event. 
a For subjects with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than 
or equal to 50% relative to baseline and lasts for at least 1 week then subjects should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion 
rate (eg, 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. See Appendix 6 for additional details. 
c Subjects with intolerable or persistent Grade 2 drug-related AE may hold pembrolizumab at physician discretion.  
Permanently discontinue pembrolizumab for persistent Grade 2 adverse reactions for which treatment with pembrolizumab 
has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
d With Investigator and Sponsor agreement, subjects with certain non-hematologic AEs (eg, alopecia, vitiligo) still at Grade 2 
after 12 weeks, may continue treatment only if asymptomatic and controlled. 
 
Treatment with pembrolizumab must occur within 3 days of the scheduled infusion day (every 3 
weeks ±2 days) unless a delay in dosing is required to allow for the resolution of AEs (see Table 
9 above). Subjects who require a delay of pembrolizumab dosing should be re-evaluated weekly 
or more frequently if clinically indicated and resume pembrolizumab dosing when re-treatment 
criteria are met as outlined in Table 8 above. If treatment with pembrolizumab is delayed by >12 
weeks from the previous dose of pembrolizumab for toxicities as outlined in Table 8, treatment 
should be discontinued after consultation with the Sponsor. 
Dosing delays lasting >12 weeks from the previous dose of pembrolizumab that occur for non-
drug-related reasons may be allowed if approved by the Medical Monitor. Prior to re-initiating 
treatment, the Medical Monitor must be consulted. Periodic study visits to assess safety should 
also continue every 6 weeks or more frequently if clinically indicated during dosing delays lasting 
>12 weeks. 


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The dose of pembrolizumab cannot be reduced in this study. 
Guidelines for the management of immune-related AEs considered by the Investigator to be related 
to pembrolizumab, are provided in Appendix 9. 
7.7. 
Concomitant Therapy 
7.7.1. 
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 
medical care. All concomitant prescription and nonprescription medications or vaccines received 
by the subject from 30 days prior to screening until 30 days after the final dose of study treatment, 
will be recorded in the electronic case report form (eCRF) along with: 
• generic name of the medication 
• reason for use 
• dates of administration including start and end dates 
• dosage information including dose and frequency 
Any addition, deletion, or change in the dose of these medications will also be recorded. 
If a subject develops intolerance or an AE to ampicillin and/or trimethoprim/sulfamethoxazole on 
study for Lm prophylaxis, another antibiotic to which Lm is typically sensitive may be substituted 
upon discussion with and approval from the Sponsor (eg, erythromycin or fluoroquinolone). 
In addition, any anti-cancer treatment received by the subject for 1 year following the final dose 
of study treatment (during the survival/treatment follow-up period), will be recorded in the eCRF, 
along with the information listed above. 
Medications specifically prohibited in the exclusion criteria (Section 6.2) and Section 7.7.2 are 
not allowed during the ongoing study. If there is a clinical indication for a medication specifically 
prohibited during the trial, discontinuation from study treatment may be required. 
Palliative and supportive care is permitted during the course of the trial for underlying medical 
conditions and management of symptoms. Surgery or radiotherapy for tumor control is not 
permitted during the study; however, radiotherapy or procedures for symptom management is 
allowed. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or prior 
therapy. 


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7.7.2. 
Prohibited Medications/ Therapy 
Subjects are prohibited from receiving the following therapies during the screening and treatment 
phases of this trial: 
• Anti-cancer systemic chemotherapy, immunotherapy, targeted therapy (eg, tyrosine kinase 
inhibitors), or other biological therapy (eg, anti-VEGF agents) not specified as study 
treatment in this protocol. Note: Ongoing pembrolizumab therapy will be permitted for 
subjects enrolled in Part B. 
• Surgical treatment as per consultation with the Sponsor. 
• Immunosuppressive agents (except as stated in Section 6.2). 
• Immunosuppressive doses of systemic corticosteroids (ie, >10 mg daily prednisone 
equivalent), except as stated in Section 6.2. 
• PI3K and TNFα inhibitors. 
• Any Investigational agent(s) other than that/those to be administered to the subject per 
protocol in this study. 
• Radiation therapy (except palliative radiation therapy for disease-related pain with a 
consult with the Sponsor's Medical Monitor). 
• Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study. Examples of live vaccines include, but are not limited to the 
following:  measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid 
(oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines 
and are allowed; however, intranasal influenza vaccines (eg, Flu-Mist®) are live 
attenuated vaccines and are not allowed. 
• Acetaminophen cannot be substituted for NSAIDs as pre-medication for ADXS-503. 
Subjects who, in the Investigator’s judgement, require the use of any of the aforementioned 
treatments for clinical management, should be discontinued from study treatment. Subjects may 
receive other medications that the Investigator deems to be medically necessary. 
In addition, please note the following: 
• Anti-infectives should be avoided. 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. 
• Medications described in Appendix 6, Appendix 7, or Appendix 8, Appendix 9 for the 
management of infusion reactions; acute hypotension, hypoxia, encephalopathy, organ 
toxicity, fever and constitutional symptoms; and immune-related AEs, respectively, 
should be administered as described in these guidelines. 


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7.7.3. Major and Minor Surgeries and ADXS-503 Treatment 
No formal studies of the effect of ADXS-503 on wound healing have been conducted. However, 
based on the mechanism of action of ADXS-503, it is not expected that administration of the agent 
would complicate wound healing. Therefore, a subject may initiate or resume study treatment 2 
weeks after minor surgery (ie, surgery involving little risk to the life of the subject; specifically, 
an operation on the superficial structures of the body or a manipulative procedure that does not 
involve a serious risk) if the wound has completely healed and there are no wound healing 
complications. A subject who has wound healing complications following minor surgery, received 
major surgery or requires new implants and/or devices (permitted by the protocol) during the 
course of the study, must wait a minimum of 6 weeks and must have recovered (eg, return to 
baseline or Grade ≤1) from any toxicity and/or complication before the next dose of study 
treatment. Sponsor consultation is required prior to resuming study treatment for these subjects. If 
study treatment is delayed beyond 12 weeks due to concomitant surgery, the subject may be 
discontinued from study treatment. 
7.8. 
Treatment after the End of the Study 
There is no mandated treatment following the end of the study. 
8. 
Discontinuation/ Withdrawal Criteria 
8.1. 
Discontinuation of Study Treatment 
Each subject will receive study treatment until a treatment discontinuation criterion is met. 
Treatment discontinuation criteria include: 
• Documented disease progression (radiographical per RECIST v1.1 or clinical, as 
determined by the Investigator). 
• Unacceptable toxicity. See Section 7.6. 
• Intercurrent illness that prevents the further administration of study treatment. 
• Physician determines that it is in the subject’s best interest. 
• Noncompliance with study treatment or procedure requirements. 
• Subject requires treatment with prohibited medication(s)/ therapy (see Section 7.7.2). 
• Pregnancy or breastfeeding (see Appendix 5). 
• Withdrawal of consent. 
• Death. 


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• Sponsor’s decision to terminate treatment or the study. 
• Part B and Part C: subject completes 2 years of treatment with ADXS-503 + 
pembrolizumab. Note: 2 years of study treatment is calculated from the first dose of 
pembrolizumab. 
• Subject achieves a confirmed CR, as described below. 
If a subject achieves a confirmed Investigator-assessed, RECIST v1.1-defined CR, the subject may 
receive up to 2 additional doses of study treatment after the date of confirmed CR but must 
subsequently discontinue treatment. Confirmation of CR should be performed ≥4 weeks after 
initial CR assessment. 
Subjects who achieve a confirmed CR (Parts A, B and C), as well as those subjects in Part B or 
Part C who stop trial therapy after 2 years of treatment for reasons other than disease progression 
or intolerability, may be eligible for re-treatment upon disease progression (with discussion and 
agreement between the Investigator and Sponsor). 
Section 8.1.1 provides guidelines for treating subjects beyond initial Investigator-assessed 
RECIST v1.1-defined disease progression. Section 8.1.1 also provides guidelines for confirmatory 
tumor imaging upon initial progression. 
8.1.1. Treatment after Initial Evidence of Radiologic Disease 
Progression 
Immunotherapy may produce anti-tumor effects by potentiating an endogenous cancer-specific 
immune response. The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents and can manifest as a clinical response 
after an initial increase in tumor burden or even the appearance of new lesions. Therefore, if initial 
radiological imaging on study in Part A, Part B and Part C indicates disease progression per 
RECIST v1.1, subjects may continue to receive study treatment provided the following criteria are 
met: 
• No deterioration in ECOG performance status 
• Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (eg, spinal cord compression) 
requiring urgent alternative medical intervention 
• The subject is tolerating treatment 
• Continued treatment is in the best interest of the subject, in the opinion of the Investigator 


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To mitigate against the possibility of pseudo-progression, tumor imaging must be repeated ≥4 
weeks after initial Investigator-assessed RECIST v1.1-defined disease progression in Parts A, B, 
and C to confirm PD, when the subject’s clinical condition warrants. If repeat imaging does not 
confirm PD, then treatment may continue or resume. If repeat imaging confirms initially 
documented PD and shows further progression of disease, the subject should be discontinued from 
study treatment, unless the basis for the PD assessment is enlarged tumor-draining lymph nodes in 
the presence of a target tumor reduction. In determining whether tumor burden has increased or 
decreased, Investigators should consider all target lesions as well as non-target lesions. If the repeat 
imaging confirms initially documented PD but shows no evidence of further tumor progression, 
the subject should be discontinued from study treatment, unless the Investigator considers the 
subject to be deriving clinical benefit, the Investigator considers continued treatment to be in the 
best interest of the subject, and the other criteria listed above are met. In this situation, treatment 
may continue after consultation with the Sponsor. 
Additional information, including iRECIST assessments may be provided to the Investigator to 
assist in treatment-related decisions at the time of RECIST v1.1-defined progression. 
8.1.2. Treatment/ Enrollment Stopping Rules 
Continuous medical oversight will be performed in this study. The purpose of the medical 
oversight is to identify potential safety signals that indicate continued treatment and/or further 
study enrollment may present a risk to study subjects. Observed safety signals will be discussed 
between the Sponsor and study Investigators during scheduled teleconferences. 
Treatment and/or study enrollment may be stopped based on the nature, frequency, or reversibility 
of observed toxicity. The following are examples of safety events that may require stopping study 
treatment and/or study enrollment for further Investigation by the Sponsor: 
• A rate of dose-limiting toxicity at dose level 1 in Part A or Part B that exceeds 33% 
• Evidence of invasive infection with study treatment 
• Delayed listeremia in subjects without risk factors such as implanted medical devices or 
hardware 
• A rate of toxicity or type of toxicity that is unanticipated based on prior experience with 
Lm-based immunotherapy and or/ pembrolizumab 
Study treatment and/or study enrollment may resume if deemed appropriate by the Sponsor and 
study Investigators, based on the review of cumulative study data and an evaluation of risk/ benefit. 
In dose-escalation Part A and Part B, safety data, including dose-limiting toxicities (see Section 
9.1.6) will be discussed between the Sponsor and study Investigators for dose escalation/ de-
escalation purposes during scheduled meetings. In Part B dose-expansion and Part C, toxicities 


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will be evaluated on an ongoing basis. If the aggregate rate of treatment-related toxicities that meet 
the DLT criteria (see Section 9.1.6) exceeds 33% at any time (across all subjects in Part B dose-
expansion and Part C), the findings will be discussed between the Sponsor and study Investigators, 
and further enrollment may be interrupted. Depending on the nature and grade of the toxicities and 
after assessing the risk/benefit, treatment may be adjusted to a lower dose of ADXS-503 or an 
alternative treatment schedule. 
See Section 5.1 for dose escalation rules for Part A and Part B. 
8.2. 
Discontinuation from the Study 
A subject may be discontinued from the study for any of the following reasons: 
• A subject may withdraw from the study at any time at the subject’s own request or that of 
the subject’s legally authorized representative or may be withdrawn at any time at the 
discretion of the Investigator for safety, behavioral, or administrative reasons. 
o If a subject is withdrawn from the study, the Investigator will complete and report 
the observations as thoroughly as possible up to the date of withdrawal including 
the date of last treatment and the reason for withdrawal. 
o Refer to the SoA for procedures to be completed at the time of study 
discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• Eligibility (subject doesn’t meet key eligibility criteria). 
• Study closure or termination. 
• Death. 
• Lost to follow-up. 
8.2.1. 
Withdrawal from the Study 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject has the 
right to withdraw consent from study participation at any time and for any reason without 
prejudice to his/her future medical care by the Investigator or at the Study Center. 
Only subjects who refuse all of the following methods of follow-up will be considered to have 
withdrawn consent from study participation: 
• Attendance at study visits per protocol. 
• Study personnel contacting the subject by telephone. 
• Study personnel contacting an alternative person (eg, family member, spouse, partner, 
legal representative, physician, or other healthcare provider). 


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Protocol ADXS-503-101 
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• Trial personnel accessing and reviewing the subject’s medical information from 
alternative sources (eg, doctor’s notes, hospital records). 
If the subject and/or their legally authorized representative refuses all of the above methods of 
follow-up, the Investigator should personally speak to the subject and/or their legally authorized 
representative to ensure the subject and/or their legally authorized representative understands all 
of the potential methods of follow-up.  If the subject and/or their legally authorized 
representative continues to refuse all potential methods of follow-up, the Investigator will 
document this as a withdrawal of consent in the medical record and in the eCRF. 
For a subject and/or their legally authorized representative who withdraws consent as defined 
above, study personnel may use local, regional, and national public records (in accordance with 
local law) to monitor vital status. 
8.2.2. Lost to Follow-Up 
A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
• In cases in which the subject is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 telephone 
calls and, if necessary, a certified letter to the subject’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA. 
• As protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns, these should be discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the subject should continue or discontinue study treatment. 


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• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the subject’s routine clinical management and obtained 
before signing the Informed Consent Form, may be utilized for Screening or baseline 
purposes provided the procedure meets the protocol-specified criteria. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples. 
9.1. 
Safety Assessments  
Planned timepoints for all safety assessments are provided in the SoA (Section 2). Safety 
assessments may be performed more frequently than the timepoints specified in the SoA, as 
clinically indicated. An “Unscheduled Visit” form will be used to record this additional 
information in the eCRF. 
9.1.1. Physical Examinations 
A complete physical examination will include, at a minimum, assessment of the body systems. 
Height will be measured at Screening only. Weight will be measured at all physical examination 
timepoints. 
A clinically significant finding or a worsening in a physical examination finding from the previous 
visit in the opinion of the Investigator or qualified designee will be recorded in the eCRF and 
reported as an AE. 
9.1.2. Vital Sign Measurements 
Vital signs will be measured in a semi-supine position after 5 minutes of rest and will include 
temperature, systolic and diastolic blood pressure, pulse, oxygen saturation, and respiratory rate. 
In Part A, vital signs will be monitored every 30 minutes (±5 minutes) starting immediately prior 
to each ADXS-503 infusion, until 4 hours after the end of each ADXS-503 infusion. Subsequent 
vital sign monitoring will be performed per institutional standard of care. 
In Part B and Part C, vital signs will be monitored prior to the administration of pembrolizumab 
and subsequently as per institutional standard of care until the administration of ADXS-503. Vital 
sign monitoring for ADXS-503 will then occur every 30 minutes (±5 minutes) starting 


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Protocol ADXS-503-101 
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immediately prior to each ADXS-503 infusion, until 4 hours after the end of each ADXS-503 
infusion. Subsequent vital sign monitoring will be performed per institutional standard of care. 
9.1.3. Performance Status Monitoring 
The Eastern Cooperative Oncology Group (ECOG) Performance Scale will be used to monitor 
performance status. Refer to Appendix 11 for a description of the ECOG scale. 
9.1.4. Clinical Safety Laboratory Assessments 
• All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the Laboratory Manual and the SoA. 
• The volume of blood to be collected at each timepoint for clinical safety laboratory 
assessments, can be found in the Laboratory Manual. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the subject's condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline. 
If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the etiology should be identified and the Sponsor notified. 
• If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in the subject’s clinical management or are 
considered clinically significant by the Investigator (eg, SAE or AE or treatment 
modification), then the results must be recorded in the eCRF. 
• A pregnancy test will be performed for all WOCBP. All WOCBP must have a negative 
pregnancy test within 72 hours prior to receiving each dose of ADXS-503 in Part A, or 
each dose of ADXS-503 or pembrolizumab in Parts B and C. Note: the only exception will 
be Week 2 in Part C, where a pregnancy test will not be required prior to the first 
pembrolizumab dose (pregnancy test performed prior to the first ADXS-503 dose at Week 
1). A positive urine pregnancy test must be confirmed by a serum pregnancy test (minimum 
sensitivity of 25 IU/L or equivalent units of βHCG).  If the pregnancy test is positive, the 
subject must not receive study treatment and must not be enrolled in the study. 
9.1.5. Assessment and Reporting of Adverse Events 
The definition of an AE, Event of Special Interest (ESI), and SAE can be found in Appendix 4. 


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AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the subject’s 
legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE, ESI, or SAE and remain responsible for follow-up of AEs 
that are serious, considered related to the study treatment or study procedures, or that caused the 
subject to discontinue the study treatment or the study (see Section 8). 
9.1.5.1. Time Period and Frequency for Collecting AE and SAE 
Information 
All AEs and SAEs will be collected from the signing of the ICF until 30 days after the final dose 
of study treatment or the beginning of any subsequent anti-cancer treatment, whichever occurs 
first. Reporting of ESI will begin from the date of first dose of study treatment. In Part A and Part 
B, ESI will be reviewed as they are reported and will be discussed at the time of the dose escalation 
meetings, and periodically afterwards. In Part C, ESI will be reviewed and discussed on an ongoing 
basis. 
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the eCRF, 
not the AE section. 
All SAEs and ESI will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix 4. The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE in former study subjects. However, if 
the Investigator learns of any SAE, including a death, at any time after a subject has been 
discharged from the study, and he/she considers the event to be reasonably related to the study 
treatment or study participation, the Investigator must promptly notify the Sponsor (ie, within 24 
hours). Furthermore, if the Investigator becomes aware of any instances (eg, blood tests performed 
at another medical facility) in which a subject has Lm isolated from a blood culture or develops an 
illness consistent with an Lm infection, the Sponsor must be notified within 24 hours of the 
Investigator becoming aware of the event. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 4. 
Adverse reactions will be reported to FDA according to 21 CFR 312.32. 
Toxicity will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) v4.03. 


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9.1.5.2. Method of Detecting AEs, ESIs, and SAEs 
Care will be taken not to introduce bias when detecting AEs, ESIs, and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
9.1.5.3. Follow-Up of AEs, ESI and SAEs 
After the initial AE/SAE report, the Investigator is required to follow each subject at subsequent 
visits/contacts. All AEs, SAEs, and ESI (as defined in Appendix 4), will be followed until 
resolution, stabilization, the event is otherwise explained, or the subject is lost to follow-up (as 
defined in Section 8.2.2). See Appendix 4 for additional information on follow-up procedures. 
9.1.5.4. Regulatory Reporting Requirements for SAEs 
• Prompt notification (ie, within 24 hours) by the Investigator to the Sponsor of an SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review the information and then file it along with the Investigator’s Brochure and will 
notify the IRB/IEC, if appropriate according to local requirements. 
9.1.5.5. Pregnancy and Breastfeeding 
• 
Prior to enrollment, study candidates who are WOCBP must be advised of the 
importance of avoiding pregnancy and lactation/breastfeeding during trial participation 
and the potential risk factors for an unintentional pregnancy. 
• 
All WOCBP must have a negative pregnancy test within 72 hours prior to receiving 
each dose of ADXS-503 in Part A, or each dose of ADXS-503 or pembrolizumab in 
Parts B and C. Note: the only exception will be Week 2 in Part C, where a pregnancy 


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Protocol ADXS-503-101 
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test will not be required prior to the first pembrolizumab dose (pregnancy test 
performed prior to the first ADXS-503 dose at Week 1). A positive urine pregnancy test 
must be confirmed by a serum pregnancy test (minimum sensitivity of 25 IU/L or 
equivalent units of βHCG).  If the pregnancy test is positive, the subject must not 
receive study treatment and must not be enrolled in the study. 
• 
A highly effective method of birth control must be used during study treatment and for 
at least 120 days after the final dose of study treatment (see Appendix 5). 
• 
Details of all pregnancies and lactation/breastfeeding cases in female subjects or female 
partners of male subjects, will be collected during the treatment period and for at least 
120 days after the final dose of study treatment. 
• 
If a pregnancy or lactation/breastfeeding case is reported, the Investigator should inform 
Advaxis within 24 hours of learning of the pregnancy or lactation/breastfeeding case 
and should follow the procedures outlined in Appendix 5. 
• 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
• 
In the case of pregnancy or a subject breastfeeds while taking protocol-required therapy, 
study treatment will be discontinued. 
9.1.6. Dose Limiting Toxicity Criteria 
Dose-limiting toxicity will be assessed over the initial 28 days of treatment in Part A and Part 
B for dose escalation/de-escalation decisions. Note: the DLT window will end 7 days after the 
second dose of ADXS-503 in Part A and 7 days after the second dose of ADXS-503 and 
pembrolizumab in Part B. Refer to Section 5.1 for the study design. 
The same DLT criteria will be used in both Part A and Part B. A DLT is defined as any of the 
following AEs that is judged by the Investigator to be possibly, probably, or definitely related to 
study treatment, and occurs during the DLT evaluation period described above (according to 
CTCAE v4.03). 
Grade 5 fatal adverse event 
Hematologic: 
1. Grade 4 neutropenia that lasts ≥72 hours 
2. Grade 4 febrile neutropenia of any duration 
3. Grade 3 febrile neutropenia that lasts more than 48 hours 


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4. Grade 4 thrombocytopenia 
5. Grade 3 thrombocytopenia associated with clinically significant bleeding 
6. Grade 3 hemolysis 
7. Grade 3 anemia that does not resolve to Grade ≤1 within 72 hours with supportive treatment, 
including transfusions 
Hepatic:  
1. ALT or AST >8 x ULN, regardless of duration 
2. ALT or AST >5 x and ≤8 x ULN, that fails to return to Grade ≤1 within 2 weeks despite 
medical intervention 
3. Total bilirubin >5 x ULN 
4. ALT or AST >3 x ULN and concurrent total bilirubin >2 x ULN 
Non-hematologic: 
1. Grade 4 anaphylaxis, hypotension, hypoxia, or acute respiratory distress  
2. Grade ≥3 non-hepatic or non-hematologic toxicity that cannot be controlled within 24 hours, 
with the exceptions below: 
The following Grade 3 non-hematologic toxicities will not be considered DLTs:  
a. Grade 3 nausea, vomiting and/or diarrhea lasting <3 days and reversible with medical 
intervention 
b. Grade 3 or 4 increase in amylase or lipase that persists <3 weeks and it is not 
associated with clinical or radiographic evidence of pancreatitis 
c. Grade 3 electrolyte abnormality that lasts <72 hours, is not clinically complicated and 
resolves spontaneously or responds to conventional medical intervention 
d. Grade 3 fever that lasts <72 hours, and it is not associated with hemodynamic 
compromise (including hypotension, or clinical or laboratory evidence of end organ 
perfusion impairment) 
e. Grade 3 endocrinopathy that is well controlled by hormone replacement 
f. Grade 3 tumor flare (defined as pain, irritation, or rash that localizes to the sites of 
known or suspected tumor) 
g. Grade 3 fatigue for less than 7 days 


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3. Delay of >12 weeks in treatment administration (ADXS-503 or pembrolizumab) due to 
unresolved toxicities that are possibly, probably, or definitely related to study treatment 
The occurrence of toxicities that meet the criteria listed above but occur outside of the DLT 
evaluation period, will be assessed on a continual basis and may be taken into consideration for 
future dose escalation/de-escalation decisions in Part A and Part B. Subjects in Part A and Part B 
who discontinue prior to the end of the DLT evaluation period for any reason other than toxicity 
will be replaced. Furthermore, if within the 28-day DLT period, a subject does not receive 2 doses 
of ADXS-503 monotherapy in Part A or 2 doses of ADXS-503 and pembrolizumab in Part B, the 
subject may be replaced for DLT assessment purposes. 
In Part C, toxicities will be evaluated on an ongoing basis. If the aggregate rate of treatment-related 
toxicities that meet the DLT criteria listed above exceeds 33% at any time (across all subjects in 
Part C), the findings will be discussed between the Sponsor and study Investigators, and further 
enrollment may be interrupted. See Section 5.1. 
Treatment modifications for specific toxicities are described in Section 7.6. 
Overall treatment and enrollment stopping rules for this study are described in Section 8.1.2. 
9.2. 
Clinical Safety Management 
9.2.1. ADXS-503 Treatment and Lm Management Guidelines 
9.2.1.1.  ADXS-503 Pre-Infusion Prophylactic Regimen 
From the previous clinical experience with Lm-based immunotherapies, it is anticipated that mild 
to moderate “flu-like” symptoms (eg, chills, pyrexia, nausea, vomiting, fatigue, headache, 
tachycardia and hypotension) may occur during or shortly after treatment infusion. The symptoms 
usually resolve within 2 to 4 hours after infusion without specific intervention or respond rapidly 
to limited symptomatic treatment within 30 minutes to 1 hour. 
Prophylactic medications are intended to reduce the inflammatory response. The incorporation of 
pre-medication and hydration has reduced the apparent incidence and severity of infusion-related 
symptoms. Therefore, subjects should receive the following pre-infusion regimen prior to each 
ADXS-503 infusion: 
IV Fluid Hydration: 
• Normal saline (eg, 500 mL over 30 minutes). 
Pre-Medication Regimen: 


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• Antihistamine – PO or IV (eg, diphenhydramine 25 mg or equivalent), once. 
• NSAIDs – PO (eg, naproxen 220 mg or ibuprofen 400 mg), once. 
• Antiemetic – PO or IV (eg, promethazine or ondansetron), once. 
• Histamine H2-receptor antagonist – PO or IV (eg, famotidine 20 mg or equivalent), once. 
Pre-infusion treatment should be administered on the day of dosing and be completed at least 
30 minutes prior to the start of the ADXS-503 infusion. Additional NSAID and antiemetic 
treatment should be given per the approved Product Label after the initial administration, as 
needed. The prescribed dosage of the selected NSAID and antiemetic will be at the discretion of 
the Investigator. 
Do not substitute acetaminophen for the selected NSAID for prophylactic treatment since 
acetaminophen does not have similar anti-inflammatory properties. 
9.2.1.2. ADXS-503 Infusion and Post-Infusion Monitoring 
 
Vital signs will be monitored every 30 minutes (±5 minutes) starting immediately prior to each 
ADXS-503 infusion, until 4 hours after the end of each ADXS-503 infusion. Vital signs will be 
measured in a semi-supine position after 5 minutes of rest and will include temperature, systolic 
and diastolic blood pressure, pulse, oxygen saturation, and respiratory rate (see Section 9.1.2). At 
4 hours after the ADXS-503 infusion, the Investigator must ensure that the subject is in a stable 
medical condition. If the subject is not stable, the Investigator must take action to provide 
appropriate medical care (see Appendix 6 and Appendix 7). 
In Part B and Part C, ADXS-503 will be administered approximately 60 (±15) minutes after the 
end of the pembrolizumab infusion. Before administering ADXS-503, the Investigator must 
confirm that the subject is in a stable medical condition and any ongoing AEs, if present, would 
not preclude the administration of ADXS-503. If ongoing AEs do preclude the administration of 
ADXS-503, ADXS-503 treatment must be delayed until the resolution of the AEs. 
9.2.1.3. Management of Listeria during Study Participation 
Following the completion of each ADXS-503 infusion, subjects will receive a 7-day course of 
either oral 80 mg trimethoprim / 400 mg sulfamethoxazole once daily or 160 mg trimethoprim/ 
800 mg sulfamethoxazole (DS) 3 times over the course of the 7 days, starting approximately 48 
hours after each ADXS-503 infusion. Subjects with a known allergy to sulfa drugs may receive 
ampicillin 500 mg 4 times daily for 7 days starting approximately 48 hours after each ADXS-503 
infusion. Subjects with dual hypersensitivity to ampicillin and sulfa drugs may be treated with 
erythromycin or fluoroquinolones, after agreement between the Investigator and the medical 
monitor (Section 9.2.1.3.1.1). Post-infusion antibiotics are administered to ensure the clearance of 


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Protocol ADXS-503-101 
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Lm. A subject who experiences a fever (Grade 1 or greater) 24 hours following the completion of 
the ADXS-503 infusion should be started on NSAIDs, hydration and other appropriate measures 
to treat the fever (see Appendix 7). If the fever persists or worsens 48 hours following the ADXS-
503 infusion, then oral or broad-spectrum IV antibiotics should be considered based on the 
subject’s medical condition. If the fever remains unresponsive to oral/IV antibiotics 72 hours 
following the ADXS-503 infusion, then a blood culture should be obtained to evaluate for 
listeremia and to determine the appropriate treatment course. 
If symptoms consistent with sepsis occur at any time after ADXS-503 administration, immediate 
medical attention must be sought. A microbial culture will be collected to identify the agent of 
sepsis and antibiotic sensitivity testing should be performed to confirm susceptibility. An 
infectious disease consult should be obtained for further management of these events. 
As an additional precautionary measure to ensure the clearance of Lm, a 3-week course of oral 
antibiotics (regimen as described above but for 21 days rather than 7 days) will be administered 
after the final dose of ADXS-503. The first dose will be administered at approximately 48 hours 
after the final dose of ADXS-503. 
Seven days (±3 days) after the completion of the 3-week course of oral antibiotics, a blood sample 
will be collected to culture for Lm. If this blood test cultures positive for Lm, immediate and 
intensive IV antibiotic treatment (ampicillin +/- gentamycin or other IV antibiotic regimen as 
indicated) is required. The Sponsor must be notified within 24 hours. An infectious disease consult 
should also be obtained. Based on each individual subject’s case and at the discretion of the treating 
physician, the removal of any foreign medical object that has been present since the initiation of 
ADXS-503 treatment may be warranted. 
Furthermore, if the Investigator becomes aware of any instances (eg, blood tests performed at 
another medical facility) in which a subject has Lm isolated from a blood culture or develops an 
illness consistent with an Lm infection, the Sponsor must be notified within 24 hours of the 
Investigator becoming aware of the event. 
9.2.1.3.1.1. Listeremia – Identification and Management 
ADXS-503 listeremia is confirmed only after isolation of Lm from a normally sterile site, such as 
blood or spinal fluid (in the setting of nervous system involvement). Stool samples are of limited 
use as Advaxis Lm strains are not shed and Advaxis Lm-based immunotherapies are administered 
intravenously. In addition, genotyping of the isolated Lm strain may be performed to confirm the 
isolate as ADXS-503. 
ADXS-503 listeremia can be treated with antibiotics. In preclinical studies, wild-type Lm and 
Advaxis Lm strains were susceptible to the lowest tested concentration of the following 
antimicrobial agents: ampicillin, amoxicillin, ciprofloxacin, erythromycin, gentamicin, penicillin, 


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Protocol ADXS-503-101 
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tetracycline, trimethoprim/sulfamethoxazole, and vancomycin (IV). ADXS-503 is resistant to 
streptomycin and nalidixic acid. 
9.2.1.3.1.2. Biofilm-Associated Listeremia 
Wild-type Lm is capable of forming and persisting within biofilms, including on medical devices, 
despite antibiotic treatment. Although rare, medical device-related infections such as ventriculo-
peritoneal shunt infection, peritoneovenous shunt infection, and prosthetic joint infection have 
been reported after systemic listeriosis (Charlier, 2012; Dominguez, 1994; Le Monnier, 2011; 
Winslow, 1984). ADXS-503 is expected to be highly sensitive to antibiotics such as 
trimethoprim/sulfamethoxazole, amoxicillin and ampicillin, erythromycin and fluoroquinolones 
which can be effective treatment regimens for listeremia. 
Therefore, subjects with implanted medical device(s) that pose a high risk for biofilm colonization 
and/or that cannot be easily removed, are excluded from this study. In addition, all subjects will 
receive a 7-day course of oral antibiotics beginning approximately 48 hours after each dose of 
ADXS-503 and for 3 weeks following the final dose of ADXS-503 to ensure clearance of Lm. 
The use of PI3K or TNFα inhibitors will be prohibited in this study. As the PI3K signaling pathway 
may be directly involved in the regulation of TNFα production, PI3K inhibitors could reduce TNFα 
production and increase subject susceptibility to bacterial infections (Smith, 2007). The absence 
of TNFα-mediated signaling may also enhance the potential virulence of attenuated Lm in subjects 
taking PI3K or TNFα inhibitors (Sonje, 2010).  
9.2.1.3.1.3. Antibiotic-Related Complications 
Subjects who develop complications during antibiotic administration, including but not limited to 
hypersensitivity reactions and Clostridium difficile-related diarrhea, may be appropriately 
managed with alternative antibiotics following discussion with the Sponsor. 
9.2.1.4. Management of Listeria During Follow-Up 
After completion of the treatment period that can last for 2 year, or discontinuation from study 
treatment, subjects enter the Follow-up Period. During Follow-up, subjects will be contacted 
remotely every 3 months (±2 week) for 1 year to determine whether they have experienced for 
several days the following symptoms that could potentially be associated with delayed listeremia 
and require prompt attention at the research site:  
• Fever or chills, headache, nausea, confusion or changes in alertness (for over 72 hours).  


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Protocol ADXS-503-101 
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As part of the End of Therapy procedures, upon completing the Lm surveillance period, site staff 
should instruct subjects to contact the site if they experience any of these symptoms, as applicable. 
9.2.2. Supportive Care Guidelines for ADXS-503 and Pembrolizumab 
Immunotherapies are associated with AEs that may differ in severity and duration compared to 
treatments such as chemotherapy or TKIs. Early recognition and management of AEs associated 
with immunotherapies may mitigate severe toxicity. 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
Investigator. Suggested supportive care measures for the management of AEs associated with the 
administration of ADXS-503 or pembrolizumab are outlined below. Where appropriate, these 
measures include the use of oral or intravenous treatment with corticosteroids and additional anti-
inflammatory agents if symptoms do not improve with the administration of corticosteroids.  Note 
that several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. For each AE, attempts should be made to rule out other causes, such as 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the Investigator determines an AE to be related to 
ADXS-503 or pembrolizumab. 
Note:  If after evaluation, the event is determined not to be related to a specific study treatment, 
the Investigator does not need to follow the treatment guidance (as outlined below). 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
9.2.2.1. Infusion Reactions 
Pembrolizumab and Lm-based immunotherapies have each been associated with infusion reactions 
following treatment administration (see Section 3.6.2). ADXS-503 is expected to have the same 
profile as Lm-based immunotherapies in this regard. Infusion reaction signs/symptoms typically 
occur during the treatment infusion, or shortly thereafter. Signs/symptoms of infusion reactions 
may include: allergic reaction/hypersensitivity (including drug fever); arthralgia (joint pain); 
bronchospasm; cough; dizziness; dyspnea (shortness of breath); fatigue (asthenia, lethargy, 
malaise); headache; hypertension; hypotension; myalgia (muscle pain); nausea; pruritic/itching; 
rash/ desquamation; rigors/chills; sweating (diaphoresis); tachycardia; tumor pain (onset or 
exacerbation of tumor pain due to treatment); urticaria (hives, welts, wheals); and vomiting. 
The management guidelines for subjects who experience infusion reactions associated with the 
administration of ADXS-503 or pembrolizumab are provided in Appendix 6. 


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9.2.2.2. Acute, High-Grade Hypotension, Hypoxia, Encephalopathy 
and Organ Toxicity 
Guidelines for the management of acute, high-grade hypotension, hypoxia, encephalopathy, and 
organ toxicity, can be found in Appendix 7. Additional information is provided in Section 
3.6.2.1.1. 
9.2.2.3. Management of Immune-Related Adverse Events 
9.2.2.3.1. ADXS-503 
While the hotspot mutation peptide antigens and TAAs expressed in the Lm construct are not 
expected to induce or exacerbate autoimmune toxicities, the potential for sub-acute or late-
occurring immune-related AEs exists. Therefore, immune-related AEs will be closely monitored 
for in this study, with ADXS-503 as a single agent, and in combination with pembrolizumab. 
General guidance for treating immune-related AEs considered by the Investigator to be related to 
ADXS-503, is provided in Appendix 8. 
9.2.2.3.2. Pembrolizumab 
A pattern of immune-related AEs has been defined for pembrolizumab, for which management 
guidelines have been developed. These immune-related AEs include: pneumonitis, 
diarrhea/colitis, Type 1 diabetes mellitus (T1DM), hypophysitis, hyperthyroidism or 
hypothyroidism, primary adrenal insufficiency, hepatic AEs, renal failure/ nephritis, skin 
reactions, infusion reactions (as described above), hemophagocytic lymphohistiocytosis, 
complications of allogeneic hematopoietic stem cell transplant (HSCT), and hematological 
toxicity in patients with chronic Hodgkin lymphoma (cHL). Immune-mediated adverse 
reactions reported in less that 1% of patients treated with pembrolizumab include uveitis, myositis, 
Guillain-Barre 
syndrome, 
pancreatitis, 
encephalitis, 
sarcoidosis, 
myasthenic 
syndrome/myasthenia gravis and myocarditis. Guidelines for the management of common 
immune-related AEs are provided in Appendix 9. Refer to Appendix 6 for guidelines to manage 
infusion reactions associated with pembrolizumab. 
9.2.2.4. Nausea and Vomiting 
Nausea and vomiting should be treated aggressively. Following treatment, subjects should receive 
antiemetic therapy as needed, according to standard institutional practice. Subjects should also be 
strongly encouraged to maintain liberal oral fluid intake. 
9.3. 
Treatment of Overdose 
For this study, any dose of ADXS-503 and/or pembrolizumab greater than the prescribed dose 
will be considered an overdose. 


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In the event of an overdose, the Investigator should: 
1. Contact the Sponsor’s Medical Monitor immediately 
2. Closely monitor the subject 
3. Document the quantity of the administered dose as well as the duration of the dosing in 
the eCRF 
Appropriate supportive treatment should be provided if clinically indicated. 
9.4. 
Efficacy Assessments 
9.4.1. Tumor Response-Based Assessments 
Tumor imaging will be performed by contrast-enhanced CT/MRI. Baseline tumor imaging will be 
performed within 28 days prior to the first dose of study treatment and will include CT/MRI of the 
chest, abdomen, pelvis and any additional known sites of disease. Subjects with known CNS 
metastases and subjects with signs or symptoms suggestive of brain metastasis should be evaluated 
with a CT/MRI of the brain at baseline. Subsequent tumor assessments should include CT/MRI of 
the head (for subjects with known CNS metastases), chest, abdomen, pelvis and any additional 
known sites of disease using the same imaging method used for the baseline scan. 
In Part A (ADXS-503 monotherapy), tumor imaging will be performed during Screening 
(baseline), at Week 8 (±7 days), at Week 16 (±7 days), followed by every 9 weeks (±7 days) 
thereafter, until confirmed disease progression or treatment discontinuation, whichever occurs 
later. 
In Part B dose-escalation and dose-expansion (ADXS-503 + pembrolizumab), tumor imaging will 
be performed during Screening (baseline), which corresponds to the most recent tumor assessment 
that is consistent with PD (according to RECIST v1.1) while on treatment with pembrolizumab 
monotherapy or while receiving combination therapy with pembrolizumab + platinum-based 
chemotherapy or while receiving pembrolizumab + pemetrexed as maintenance therapy, as the 
last therapy in the metastatic setting. As described above, the first dose of ADXS-503 will be 
administered within 12 weeks of the initial assessment of PD. Subsequent scans will be performed 
at Week 8 (±7 days), at Week 16 (±7 days), every 9 weeks (±7 days) after dosing with ADXS-503 
+ pembrolizumab in all Part B subjects, until confirmed disease progression or treatment 
discontinuation, whichever occurs later. 
In Part C (ADXS-503 + pembrolizumab), tumor imaging will be performed during Screening 
(baseline), at Week 8 (±7 days), at Week 16 (± 7 days), followed by every 9 weeks (±7 days) 


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thereafter, until confirmed disease progression or treatment discontinuation, whichever occurs 
later. 
Tumor imaging will occur at the schedule above, independent of any adjustments to the 
treatment schedule. 
Tumor response will be evaluated by the Investigator (or designee) according to RECIST v1.1 as 
the basis for the primary analysis of tumor response-based endpoints. Exploratory analysis of 
tumor-response will be performed by the Sponsor (or designee) according to iRECIST. 
• In Part A and Part C, subjects may receive study treatment beyond initial Investigator-
assessed, RECIST v1.1-defined disease progression, provided the criteria in Section 8.1.1 
are met. Additional information, including iRECIST assessments may be provided to the 
Investigator to assist in treatment-related decisions at the time of RECIST v1.1-defined 
progression. In Part B, all subjects will begin study treatment within 12 weeks of initial 
Investigator-assessed, RECIST v1.1-defined disease progression on treatment with 
pembrolizumab monotherapy or while receiving combination therapy with pembrolizumab 
+ platinum-based chemotherapy or while receiving pembrolizumab + pemetrexed as 
maintenance therapy, as the last therapy in the metastatic setting (if eligibility criteria are 
met). 
• For all subjects in Parts A, B and C, any apparent CR or PR must be confirmed ≥4 weeks 
after radiological imaging indicating CR or PR. 
• Subjects who achieve a confirmed CR may receive up to 2 additional doses of study 
treatment after the date of confirmed CR but must subsequently discontinue treatment (see 
Section 8.1). 
• Subjects who achieve a confirmed CR (Parts A, B and C), and subjects in Part B or Part C 
who stop trial therapy after 2 years of treatment for reasons other than disease progression 
or intolerability, may be eligible for re-treatment upon disease progression (with agreement 
between the Investigator and Sponsor) [see Section 8.1]. Tumor response data collected 
during the re-retreatment period will not be used for the primary analysis of tumor response 
endpoints. 
• All subjects who complete the first tumor scan after the first dose of study treatment, will 
be considered evaluable for tumor response. 


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The following efficacy endpoints will be evaluated from the tumor response data in Part A, Part B 
and Part C, according to RECIST v1.1 (primary analysis) and selectively, as deemed appropriate 
by iRECIST (exploratory analysis) (see Section 10.3 and Appendix 10): 
• Best overall response (BOR) 
• Objective response rate (ORR) 
• Duration of objective response (DOR) 
• Disease control rate (DCR)  
• Progression-free survival (PFS) 
• PFS rate at 12 months 
Please refer to Section 10.3 for the definition of tumor response-based endpoints and their analysis. 
9.4.2. Survival Assessments 
All subjects will be assessed for survival status from study enrollment until approximately 1 year 
after the final dose of study treatment. Following treatment discontinuation, survival status will be 
confirmed remotely with the subject, their physician, or their legally authorized representative 
every 3 months (±2 weeks) for up to 1 year. 
The following efficacy endpoints will be evaluated from the survival data in Part A, Part B and 
Part C: 
• Overall survival (OS) 
• 6- and 12-month overall survival rates 
Please refer to Section 10.3 for the definition of survival endpoints and their analysis. 
9.5. 
Biomarker Assessments 
• Blood and tumor tissue samples for biomarker research will be collected at the time points 
specified in the SoA. 
• The volume of blood and tissue to be collected for biomarker analysis, and processing and 
shipping instructions, can be found in the Laboratory Manual. 
• Blood and tumor tissue samples may be stored for a maximum of 5 years following the last 
subject’s last study visit at a facility selected by the Sponsor to enable further analysis of 
the samples. 
• Blood Sampling for Exploratory Correlates of Immune Response in Parts A, B and C 
o In Part A, Part B and Part C, peripheral blood may be collected at Screening and 
during the treatment phase of the study at the time points specified in the SoA. 


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Peripheral blood mononuclear cells (PBMCs) and sera will be prepared for the 
planned immune correlative analyses, as outlined in Section 9.5.1 below. 
• Tumor Biopsy Sampling 
o Exploratory Biomarker Evaluation in Part A, Part B & Part C  
▪ Baseline biopsy sample: All subjects must consent to allow the acquisition 
of fresh or archival FFPE tumor tissue, either a block or unstained slides 
along with matching blood at baseline, for performance of sequencing 
analysis. A fresh tumor biopsy sample must be collected within 28 days (±2 
days) prior to the first dose of study treatment (baseline) in Part A and 
within 6 weeks in Part B, where feasible, in the opinion of the Investigator. 
If a fresh tumor biopsy sample cannot be obtained, the most recently 
acquired archived tumor biopsy sample may be used for analysis. For 
archived tumor biopsy samples, sufficient tumor samples should be 
acquired to allow sequencing analysis (eg, at least unstained 12-15 slides). 
The archived sample must have been biopsied within 3 years of Screening. 
The baseline tumor biopsy sample (fresh or archived) must be from a 
location that has not been radiated. 
▪ Baseline tumor biopsy samples and matching blood for sequencing analysis 
will be evaluated in all patients in the study as outlined in Section 9.5.1 
below. 
o Required Specimen Evaluation for Eligibility in Part C 
▪ Participation in Part C of this trial will be dependent upon supplying tumor 
tissue from a location that has not been radiated. Subject must consent to 
allow the acquisition of fresh or archival FFPE tumor tissue, either a block 
or unstained slides along with matching blood at baseline, for performance 
of sequencing analysis. Biopsies obtained PRIOR to receipt of 
neoadjuvant/adjuvant chemotherapy are NOT permitted. The tumor tissue 
must have been previously evaluated for expression status of PD-L1 at a 
local laboratory facility using FDA-approved tests. Fine needle aspirates, 
Endobronchial Ultrasound (EBUS) or cell blocks are not acceptable. Needle 
or excisional biopsies, or resected tissue is required. If the tumor specimen 
is not evaluable for PD-L1 expression, an additional tumor specimen must 
be submitted to the local laboratory facility for testing with FDA approved 
assays before enrolling. Only subjects whose tumors express PD-L1 (TPS 


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≥1%), as determined by an FDA-approved test will be eligible for 
enrollment. 
▪ In Part C, documentation of EGFR mutation and/or ALK translocation status 
will be required for subjects with non-squamous NSCLC AND if clinically 
indicated. If the site is unable to provide this source documentation, EGFR/ 
ALK testing should be performed per institutional standard of care using 
FDA-approved tests. 
9.5.1. Biomarker Evaluation in Part A and Part B 
In Part A and in up to a total of 25 patients from Part B and Part C, peripheral blood will be 
collected at Screening and during the treatment phase of the study for correlative work at the time 
points specified in the SoA (Section 2). Peripheral blood mononuclear cells (PBMCs) and sera 
will be prepared for the planned immune correlative analyses. 
Immune Cell Phenotype 
Flow cytometry will be performed on isolated PBMCs to examine the states of 
activation,differentiation and cytotoxicity of  various immune cells in Patients from Part A and in 
up to a total of 25 patients from Part B and/or Part C.  
Monitoring of T Cell Responses 
At baseline and during treatment in in up to 25 patients from dose-escalation Part A and Part B 
and Part C, the frequency of functional tumor antigen-specific T cells will be quantified by 
FluoroSpot in peripheral blood samples.  
Genetic Alterations in Tumor Cells, Tumor Microenvironment and T cells  
DNA and RNA from FFPE specimens and matching blood samples will be analyzed by whole 
exome sequencing and RNA sequencing in Parts A, B and C at baseline. These assays will 
determine the expression pattern of the hotspot mutations and the tumor-associated antigens, 
which are included in ADXS-503, in each subject’s tumor, to identify subject-specific mutation-
derived antigens, and to determine the subject’s tumor mutational burden, microsatellite status, 
TCR repertoire, and haplotypes.  
9.6. 
Pharmacokinetic Assessments 
Blood samples for pharmacokinetic analysis will not be taken in this study. Pharmacokinetic 
parameters will not be evaluated. 


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9.7. 
Pharmacodynamic Assessments 
Pharmacodynamic parameters other than biomarkers described in Section 9.5, will not be 
evaluated in this study. 
9.8. 
Pharmacogenomic Assessments 
Pharmacogenomic parameters will not be evaluated in this study. 
9.9. 
Health Economics OR Medical Resource Utilization and Health 
Economic Assessments 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
10. 
Statistical Considerations 
10.1. 
Sample Size Determination 
Safety Phase 
Up to approximately 24 subjects will be enrolled in the safety phase in either Part A or Part B 
dose-escalation. 
In Part A, up to approximately 12 subjects will receive treatment with ADXS-503 monotherapy at 
1 of 2 planned escalating dose levels. In Part B dose-escalation, up to approximately 12 subjects 
will receive treatment with ADXS-503 at 1 of 2 planned escalating dose levels in combination 
with a fixed dose of pembrolizumab. A 3+3 design will be used for dose escalation/ de-escalation 
purposes in Part A and Part B. 
The sample size in Part A and Part B dose-escalation/de-escalation is not based on statistical 
considerations and will be determined by safety data and DLTs observed at each dose level 
evaluated. 
Upon completion of dose escalation in Part A, ADXS-503 monotherapy may be evaluated in an 
expansion cohort. Up to approximately 25 subjects may be enrolled in this expansion cohort. 
Efficacy Phase 
In the efficacy phase (Part B dose-expansion and Part C), up to approximately 165 subjects may 
be enrolled. Up to 43 subjects may be enrolled in Part B expansion of DL1 in the Simon’s Two-
stage study cohort and up to a total of 140 thereafter. In addition, approximately up to 25 subjects 
may be enrolled in Part C. 


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The sample size in Part B dose-expansion at dose level 1 (DL-1) will use Simon's optimal Two-
stage design (Simon, 1989). The null hypothesis is that the true response rate is 0.1, and the 
alternative hypothesis is that the true response rate is 0.25. The Part B dose-expansion will be 
carried out in 2 stages. In stage I, a total number of 18 subjects is accrued. If there are 2 or fewer 
responses among these 18 patients, the study will be stopped early. Otherwise, an additional 25 
patients will be accrued in stage II, resulting in a total sample size of 43 subjects. If there are 8 or 
more responses among these 43 subjects, we reject the null hypothesis and claim that the treatment 
is promising. The design controls the type I error rate at 0.05 and yields a power of 0.8. 
 
r1 
n1 
r 
n 
Type I error 
Power 
PET(p0) 
EN(p0) 
Optimal 
2 
18 
7 
43 
0.48 
0.8003 
0.7338 
24.7 
Note: r1 = the first stage threshold to stop the trial for futility; n1 = number of accrual subjects for stage I; n = total 
number of subjects; r = overall threshold to stop the trial for futility; EN(p0) = expected sample size for the cohort 
when the true response rate is p0; PET(p0) = probability of early termination when the true response rate is p0. 
In Part C, approximately 25 subjects will be enrolled and will receive treatment with ADXS-503 
in combination with pembrolizumab. The sample size in Part C is not based on statistical 
considerations but is considered sufficient to evaluate the preliminary clinical efficacy of the 
treatment combination. 
Additional subjects may be enrolled in the study based on emerging study data or the evolving 
treatment landscape. In this situation, the protocol will be amended accordingly to reflect the 
sample size and relevant statistical analyses. 
10.2. 
Populations for Statistical Analyses 
For purposes of statistical analysis, the following populations are defined (see Table 10): 
Table 10: Populations for Statistical Analysis 
Population 
Description 
All Enrolled Subjects 
All subjects who sign the ICF, meet entry criteria and are allocated a 
slot in the study. 
All Treated Subjects 
All subjects enrolled in the study who receive at least one dose of study 
treatment.   
Tumor Response Evaluable 
Subjects 
All subjects in the All Treated Subjects population with at least one 
post-baseline evaluable tumor scan. 


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10.3. 
Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized before database lock to provide 
full details on the study populations, endpoint definitions, analyses and methods. 
Summary statistics for continuous variables will include mean, standard deviation, median and 
range. Categorical variables will be presented as frequency counts and percentages; and time-to-
event variables will be summarized by Kaplan-Meier (KM) medians and survival plots. Data 
listings will be created to support tables and figures and to present data. 
Below is a summary of the planned statistical analyses to support the endpoints of this study. 
10.3.1. Analysis of Safety 
All safety analyses will be performed on All Treated Subjects and summarized by dose level and 
study part. 
Adverse events will be summarized (incidence) and listed by the System Organ Class (SOC), 
preferred term, toxicity/severity grade, and Investigator-assigned relationship to study treatment.  
In addition, separate summaries of SAEs, ESIs and Grade 3 and 4 AEs will be presented. 
Tabulations will be limited to treatment emergent events – ie, those with onset anytime during 
study treatment through 30 days after the final dose of study treatment or the beginning of 
subsequent any anti-cancer treatment, whichever occurs first; or if they were present prior to the 
first dose of study treatment and worsened during study treatment as specified above. 
Hematological and chemistry laboratory parameters will be graded according to the CTCAE v.4.03, 
where applicable. Shifts from baseline in severity grade will be tabulated. Absolute values and 
changes from baseline will be summarized. 
Vital sign measurements and the corresponding changes from baseline will be summarized using 
descriptive statistics. 
Results of performance status and physical examinations will be presented in the subject data 
listings. 
10.3.2. Analysis of Efficacy 
All efficacy analyses will be performed on All Treated Subjects and summarized by dose level and 
study part.  
Efficacy endpoints will be descriptively summarized by dose level and study part. Tumor response 
will be summarized according to response category. Objective response rate (ORR) and disease 
control rate (DCR) will be summarized by frequency tables. The KM method will be used to 
estimate progression-free survival (PFS), PFS rate at 12 months, overall survival (OS) and 


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Protocol ADXS-503-101 
114 
milestone OS rates at 6 and 12 months. Descriptive statistics and KM curves will also be presented. 
Actual tumor response results may render exploratory evaluation by the iRECIST criterion 
unnecessary or superfluous, such as when the difference between results using RECIST v1.1 and 
iRECIST criteria is small or insignificant.  In such a case, selected efficacy endpoints by iRECIST 
as stated below may not be conducted. 
10.3.2.1. Best Overall Response 
Best overall response (BOR) will be evaluated for All Treated Subjects, and if warranted, for 
Tumor Response Evaluable Subjects according to RECIST v1.1 and iRECIST. 
Best overall response is determined based on tumor assessments recorded between the first dose 
of study treatment and the date of first objectively confirmed disease progression, or the date of 
subsequent anti-cancer treatment, whichever occurs first. For subjects without confirmed disease 
progression or subsequent anti-cancer treatment, all available response designations will 
contribute to the BOR assessment. 
10.3.2.2. Objective Response Rate 
Objective response rate will be evaluated for All Treated Subjects, and if warranted, for Tumor 
Response Evaluable Subjects according to RECIST v1.1 and iRECIST. Objective response rate is 
defined as the proportion of subjects who achieve a CR/iCR or PR/iPR as BOR. 
CR or PR determinations included in the BOR assessment must be confirmed by a confirmatory 
scan ≥4 weeks after the criteria for response are first met. 
10.3.2.3. Duration of Objective Response 
Duration of objective response will be evaluated for subjects who have a BOR of CR or PR per 
RECIST v1.1, or a BOR of iCR or iPR per iRECIST. Duration of objective response is defined as 
the time from the date when the criteria are first met for a CR/iCR or PR/iPR to the first date that 
disease progression is objectively documented, or death regardless of cause, whichever occurs 
first. 
For subjects who neither progress nor die, the duration of objective response will be censored at 
the same time as the primary definition of PFS. 
10.3.2.4. Disease Control Rate 
Disease control rate will be evaluated for All Treated Subjects, and if warranted, for Tumor 
Response Evaluable Subjects according to RECIST v1.1 and iRECIST. Disease control rate is 
defined as the proportion of subjects who achieve a CR/iCR, PR/iPR or SD/iSD ≥24 weeks as 
BOR (as defined above). 


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10.3.2.5. Progression-Free Survival 
Progression-free survival will be evaluated for All Treated Subjects according to RECIST v1.1 
and iRECIST. Progression-free survival is defined as the time from the date of the first dose of 
study treatment to the date of the first objectively confirmed radiographic disease progression, or 
death regardless of cause, whichever occurs first. 
Clinical deterioration in the absence of objectively confirmed progression is not considered 
progression for the purpose of determining radiographic PFS. Subjects who die without a reported 
progression will be considered to have progressed on the date of their death. Subjects who do not 
progress or die will be censored on the date of their last evaluable tumor assessment. Subjects who 
do not have any on-study tumor assessments and do not die will be censored on the date of the first 
dose of study treatment. Subjects who start any subsequent anti-cancer therapy, without a prior 
reported progression will be censored at the last evaluable tumor assessment prior to initiation of 
the subsequent anti-cancer therapy. 
10.3.2.6. Progression-Free Survival Rate at 12 Months 
Progression-free survival rate at 12 months will be evaluated for All Treated Subjects according 
to RECIST v1.1 and iRECIST. Progression-free survival rate at 12 months is defined as the KM 
probability of PFS at 12 months. 
10.3.2.7. Overall Survival 
Overall survival will be evaluated for All Treated Subjects. Overall survival is defined as the time 
from the date of the first dose of study treatment to the date of death, regardless of cause. If no 
death date is known for a subject, OS will be censored at the date the subject is last confirmed to 
be alive. 
10.3.2.8. Milestone Overall Survival Rate at 6 and 12 Months 
Milestone survival will be evaluated for All Treated Subjects. Milestone survival is defined as the 
KM survival probability at 6 and 12 months after the date of the first dose of study treatment. 
10.3.3. Biomarker Analyses 
The analysis of biomarker endpoints will be described in the SAP that is finalized before database 
lock. The results of biomarker data may be presented separately from the main clinical study report 
(CSR). 


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10.3.4. Interim Analyses 
No formal interim analysis is planned for this study. Administrative interim analyses on safety 
and efficacy may be conducted prior to the completion of the study in order to facilitate program 
decisions and to support study presentations or publications. 


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11. 
Regulatory 
See Appendix 3 for information regarding regulatory and ethical considerations, including 
financial disclosure, informed consent process, data protection, publication policy, dissemination 
of clinical study data, data quality assurance, source documents, and study and site closure. 


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The Cancer Genome Atlas [TCGA]. (2014). Comprehensive molecular profiling of lung 
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13. 
Summary of Changes Within Protocol Amendment 4 
# 
Section 
Revision 
Rationale 
1 Throughout 
• Editorial changes and corrections 
• Part B: includes 2 parts: dose-escalation (part of Safety Phase) and dose-expansion of 
dose level 1 (part of Efficacy Phase). Part B-escalation to DL2 is contingent upon 
sponsor’s decision to commence this segment of the study. 
• Revised text and Figure 1 to reflect updated expansion phase of Part B DL1 
• Part B and Part C: Clarification of eligibility criteria and use of same timepoints for tumor 
scans and biomarkers in both parts, as priming with ADXS-503 before pembrolizumab is 
no longer needed in Part C.  
• Part B and Part C: Reduced biomarker plan with reduced collection of blood samples, 
mandatory tumor tissue at baseline (archival or fresh) and no on-therapy biopsies  
• To provide additional clarity 
• To expand on prior plans of 
extending investigations of the 
efficacy signals seen in Part B 
safety phase in a dose-
expansion efficacy phase, with 
further details added for clarity 
in this regard. Accrual in Part 
B DL2 may occur pending 
Sponsor decision, however, 
accrual is ongoing in the 
efficacy portions of the study. 
• Confirmatory scans of 
progression are mainly used in 
research studies to characterize 
primary and secondary 
resistance in pts failing 
checkpoint inhibitor (CPI) 
therapy. But, in the clinic, it is 
not always feasible or practical 
to wait for another scan to start 
rescue therapy just to try to 
document 
“pseudoprogression”, which 
happens in 5% of pts.   
2 Trial Summary/ 
2.2/Figure 1/ 
4/5.1/5.1.3/6.1/ 
9.4.1 
Appendix 2 
Part B : Revised dose-expansion eligibility criteria: 
• Screening (baseline), which corresponds to the most recent tumor assessment that is 
consistent with PD (according to RECIST v1.1) while on treatment with pembrolizumab 
monotherapy as last treatment, or while receiving combination therapy with 
pembrolizumab + platinum-based chemotherapy as last treatment or pembrolizumab + 
pemetrexed as maintenance therapy, as last treatment in the metastatic setting. 
• Subjects receiving pembrolizumab + platinum-based chemotherapy or pembrolizumab + 
pemetrexed, will continue pembrolizumab monotherapy every 3 weeks; other drugs 
• Clarification of patient 
population enrolled, 
especially given recent 
changes in treatment standard 
landscape and 
pembrolizumab’s 
approvals/PI updates. Thus, 
allowing subjects undergoing 
or completed pembrolizumab 


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washed-out for 3 weeks. 
• No evidence of rapid disease progression/clinical deterioration that would preclude 
continuation of pembrolizumab monotherapy for up to 12 weeks before ADXS-503 is 
added-on. Expansion of the eligibility window from 4 to 12 weeks for refractory patients 
that progress on pembrolizumab as last treatment 
Part B and Part C:  
• Added: Mandatory fresh or archival formalin-fixed paraffin embedded (FFPE) tumor 
tissue, either a block or unstained slides along with a matching blood at baseline, for 
performance of sequencing analysis. 
• Blood samples for exploratory immune correlative studies (eg, RNAseq, cfDNA, flow 
cytometry and ELISPOT analysis) may be collected in up to 25 total patients from Part B 
and Part C during Screening, at Week 1, 2, 5, and 8. To monitor the durability of T cell 
responses, subsequent blood samples for PBMCs may be taken at Week 25 (±1 week) 
and/or at end of treatment.  
• Language removed from inclusion criteria Table 3 for coagulation testing: ”PT/INR and 
aPTT must be measured during Screening. Subsequent testing is to be performed only as if 
clinically indicated”. 
Part C:  
PD-L1 expression in baseline tumor samples changed from ≥50% to Tumor Proportion Score 
(TPS) ≥1% as determined by an FDA-approved test 
+ platinum-based 
chemotherapy or currently 
receiving pembrolizumab + 
pemetrexed as their last 
therapy 
• Coagulation times will not be 
part of eligibility criteria. 
There have been no reports of 
coagulation abnormalities 
associated with 
administration of Lm 
constructs in legacy studies 
nor in the safety phase of this 
study. However, the 
coagulation times can be 
evaluated at any timepoint by 
the Investigator, as clinically 
indicated. 
• PD-L1 TPS ≥1% is FDA 
approved for the use of 
pembrolizumab in first line 
therapy of NSCLC 
3 Trial Summary/ 
2.2/ 
3.5/5.1/5.1.3/6.1/ 
9.4.1 
In Part B, administer ADXS-503 first dose within 12 weeks of initial tumor assessment 
showing PD (on pembrolizumab monotherapy, pembrolizumab + platinum-based 
chemotherapy and/or pembrolizumab + pemetrexed). 
Consistent with current clinical 
practice.  
4 Trial Summary/ 
Figure 1/5.1.1 
Part B: Accrual in DL1 dose-expansion and Part C will occur in parallel, and updating 
Figure with changes related to Part B dose-escalation and expansion  
Clarification 
5 Trial Summary/2.2/4 
Part C: Included in Exploratory objectives of correlative studies.  
Clarification 


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6 Trial Summary/ 
2.1/2.2/ 5.1.2/7.1.1/ 
7.1.2/7.1.3/9.2.1.3/ 
9.2.1.3.1.2 
Oral antibiotics will be administered starting approximately 48 hours after each ADXS-503 
infusion instead of 72 hours. 
To further decrease the risk of 
formation of  listeria biofilms on 
allowed medical devices and/or 
in the development of  delayed 
listeremia. ADXS-503 is an Lm-
based immunotherapy that is 
rapidly cleared from the blood 
and not detectable beyond 48 
hours post dose, even without 
the use of antibiotics. There is 
evidence to suggest 
immunogenicity can be elicited 
within this period of time and it 
is not necessary to wait 72 hours 
to start antibiotics. 
7 Trial Summary/ 
5.1/5.1.3/6.1/9.4.1 
Part B: (dose-escalation and dose-expansion) screening/ baseline tumor imaging is most 
recent tumor assessment consistent with progressive disease (PD) according to RECIST v1.1 
while receiving pembrolizumab alone, pembrolizumab + platinum-based chemotherapy or 
pembrolizumab + pemetrexed as maintenance therapy, after platinum-based chemotherapy in 
the metastatic setting. 
To confirm PD while on therapy 
with  pembrolizumab 
monotherapy or in combination 
therapies. Definition of PD by 
RECIST v1.1 is standard 
clinical practice  
8 Trial Summary/ 
9.4.1 
Part B: Screening (baseline), which corresponds to the most recent tumor assessment that is 
consistent with PD (according to RECIST v1.1) while on treatment with pembrolizumab 
monotherapy as last treatment, or while receiving combination therapy with pembrolizumab + 
platinum-based chemotherapy or pembrolizumab + pemetrexed as maintenance therapy, as 
last treatment in the metastatic setting. Subsequent scans will be performed in all subjects at 
Week 8 (±7 days), at Week 16 (± 7 days), followed by every 9 weeks (±7 days) after the start 
of ADXS-503 + pembrolizumab until confirmed PD or treatment discontinuation, whichever 
occurs later. 
Part C: After Screening, at Week 8 (±7 days), at Week 16 (± 7 days), followed by every 9 
weeks (±7 days) after the start of ADXS-503 + pembrolizumab until confirmed PD or 
treatment discontinuation, whichever occurs later. 
 
 
Standard of clinical practice  
Scans are now conducted at 
similar timepoints in Part B and 
Part C. Data from Part B 
suggests that there is no need to 
prime Part C patients with 
ADXS-503 one week in advance 
of the first dose of 
pembrolizumab. Hence, both 
drugs will start on Week 1 in 
patients from Part C as it has 
been done for Part B patients.  
 
   


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9 Trial Summary/2.2/ 
5.1.3/6.1/8.1.1/9.4.1 
• Parts A, B, and C: Deleted Tumor imaging must be repeated ≥4 weeks after initial PD 
while on therapy. 
• Removed: In Part A and Part C, tumor imaging must be repeated ≥4 weeks after initial 
Investigator-assessed, RECIST v1.1-defined disease progression, to confirm PD, when the 
subject’s clinical condition warrants (see Section 8.1.1 and Section 9.4.1). In Part B, a 
confirmatory scan will be performed between 4-8 weeks after the initial assessment of PD 
on treatment with pembrolizumab monotherapy (to confirm PD or determine CR, PR or 
SD), as described above. 
Part B: Deleted requirement for confirmatory scan 4-8 weeks after the initial assessment 
of PD on pembrolizumab monotherapy. Following language was removed: 
• “Only subjects who have progressed within 6 months of starting pembrolizumab 
monotherapy may require a confirmatory scan within 4-8 weeks after the initial scan 
showing PD before starting ADXS-503, if the Investigator considers it necessary. ….” 
• Subjects will receive at least four weeks of treatment with ADXS 503 plus pembrolizumab 
before the new confirmatory scan is done. Based on the computer scan the decision is 
made to continue study treatment” Under eligibility criteria, “Only subjects who have 
progressed within six months of starting pembrolizumab monotherapy may require a 
confirmatory scan within four - eight weeks after the initial scan showing PD and before 
starting advances 503, if the investigator considers it necessary “, has been removed 
 
Confirmatory scans of PD are 
not mandatory in patients  
progressing while on checkpoint 
point inhibitor (CPI) as last 
therapy. Confirmatory scans are 
used in clinical research to 
characterize primary and 
secondary resistance to CPIs 
(Kluger H et.al.. Journal for 
ImmunoTherapy of Cancer 
2020). The scans can define 
“pseudo progression” in the 
former category, which is an 
event that only happens in 5% of 
patients. And it is unlikely that 
pts with secondary resistance -
who have had a response to 
CPIs for more than 6 months 
and which is the case for most 
of our patients in Part B- will 
now have  
10 Trial Summary 
2/2.2/5.1.3/6.1/9.5 
Parts A, B, and C: Blood and biopsy samples may be collected for correlative studies. For all 
Part B and Part C patients: Mandatory fresh or archival formalin-fixed paraffin embedded 
(FFPE) tumor tissue, either a block or unstained slides along with a matching blood at 
baseline, for performance of sequencing analysis. 
Added, “During Screening for subjects in Part B and Part C tumor tissue collection with 
matched blood at screening is mandatory for all patients in the study. A fresh tumor biopsy 
must be obtained if clinically feasible, in the opinion of the Investigator for biomarker 
analysis. If a fresh biopsy cannot be obtained during Screening, the most recently acquired 
archived tumor biopsy sample may be used for analysis (date of biopsy within 3 years of 
Screening). The baseline biopsy must be from a location that has not been radiated. Sufficient 
tumor samples should be acquired to allow biomarker testing (eg, at least unstained 12-15 
unstained slides). Tumor tissue and matching blood samples collected during Screening will 
be used for sequencing analysis”. 
 
On-therapy tumor tissues biopsies will no longer be collected between weeks 5-9 in Part B or 
C. 
Selection of most informative 
biomarker assessments/ 
correlative work for exploratory 
objectives, and clarifications of 
current text.  
It has been challenging to 
collect on-therapy biopsies due 
to the nature and localization of 
the tumors and the benefit/risk 
ratio is low.  
Age of archival biopsy accepted 
for eligibility has been extended 
from 2 to 3 years to provide 
flexibility. 


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Blood samples for exploratory immune correlative studies (eg, RNAseq, cfDNA, flow 
cytometry and ELISPOT analysis) may be collected in up to 25 total patients from Part B and 
Part C during Screening, at Week 1, 2, 5, and 8. To monitor the durability of T cell responses, 
subsequent blood samples for PBMCs may be taken at Week 25 (±1 week) and/or at end of 
treatment. 
Evaluation of cytokines, 
FluoroSpot, 
immunohistochemistry of PD-
L1 at a central lab and multiplex 
immunofluorescence will no 
longer be performed.  
11 Trial Summary 
2.2/6.1 
Part B and Part C: Clinical site must provide documentation of tumor PD-L1 expression and 
EGFR mutation and/or ALK translocation status as evaluated by FDA-approved tests in all 
patients.  Baseline tumor samples must express PD-L1 [TPS (Tumor Proportion Score) ≥1%] 
as determined by an FDA-approved test at a local laboratory facility, with no EGFR or ALK 
genomic tumor aberrations for subjects to be eligible for Part C. If the site is unable to provide 
this source documentation, PD-L1 expression and/or EGFR/ALK testing should be performed 
per institutional standard of care (see Section 9.4.1 and Section 9.5). 
Clarification that PD-L1 
expression can be documented 
from the medical records and-if 
not available- to do so by 
running the test in baseline 
tumor samples at a local 
laboratory facility using FDA 
approved tests.  No central 
laboratory is currently needed to 
test PD-L1, because it is 
standard of care.   
12 2.2/9.5 
Part C: Clinical site must provide documentation of tumor EGFR mutation and/or ALK 
translocation status for subjects with non-squamous NSCLC, AND if clinically indicated. If 
the site is unable to provide this source documentation, EGFR/ALK testing should be 
performed per institutional standard of care. 
Clarification 
13 2.2/9.5 
Part B: dose-expansion: removed Blood samples for cytokine/chemokine and FluoroSpot 
analyses at Screening and on-therapy.   
 
 
 
 
 
 
 
 
 
Cytokines were relevant to 
evaluate safety during dose 
escalation.FluoroSpot assays in 
dose escalation and -in some pts 
in Part B dose expansion- 
further documented MOA. 
Collection of blood for 
FluoroSpot and cytokines/ 
chemokines are therefore  no 
longer needed, reducing blood 
collection by ~ 160 mL during 
the course of therapy. 
Exploratory objectives 


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14 2.2/ 9.5 
Part B dose-expansion and Part C: Blood samples for exploratory immune correlative 
studies (eg, RNAseq, cfDNA, flow cytometry) may be collected in up to 25 total patients from 
Part B and Part C during Screening, at Week 1 (ie, right before the first infusion) and 7 days 
(±2 days) after the end of each of the first 3 ADXS-503 infusions (Weeks 2, 5, and 8) and 
EOT. Samples for cfDNA are only collected at week 1 if samples are not collected during 
screening. To monitor the durability of T cell responses, subsequent blood samples for 
PBMCs may be taken at Week 25 (±1 week) and/or at end of treatment 
Optimized exploratory 
objectives focusing in 
sequencing and flow cytometry 
analyses of peripheral blood at 
baseline and on-therapy.  These 
will be correlated with 
sequencing analysis of the 
matching tumor tissue at 
baseline  
15 2.3 
Deleted as Combined SoA of Part B and Part C  
Evaluation of Scans and 
Biomarkers is now conducted at 
the same timepoints as there is 
no longer priming with ADXS-
503 one week in advance of 
dosing pembrolizumab in Part C 
patients.  
16 3.4.4/3.5  
Updated clinical experience and safety data from the ADXS-503-001 Trial 
To ensure availability of up-to-
date data  
17 4 
Part B: Added “dose escalation” to safety objectives 
Clarification 
18 4/5.1.1 
Part B: Added “dose expansion” to efficacy objectives. 
Clarification 
19 4 
Part C: Added to objective to characterize subject immunological activity and genomic 
profiles 
Exploratory objectives 
20 5.1.2/ 10.1 
Part B: Added Part B dose-expansion to Efficacy Phase 
Part B expansion – Expanding the patient population and enrollment based on Simon’s Two-
stage design, where at Stage I of Simon’s design, 18 subjects will be accrued in this study 
arm. Sponsor may decide to accrue additional 25 subjects for a total of 43 patients in Stage II.  
Part B study objectives - Include evaluation of preliminary antitumor activity of ADXS- 503 
plus pembrolizumab as a primary objective 
In the efficacy phase (Part B-dose expansion and Part C combined), up to approximately 165 
subjects may be enrolled. In Part B dose expansion, up to 43 subjects will be enrolled in the 
Simon’s Two-stage study cohort and up to a total of 140 thereafter. Approximately up to 25 
subjects may be enrolled in Part C 
Clarification 
To better characterize the safety, 
tolerability and early clinical 
activity of the combination 
therapy in patients failing 
pembrolizumab as last therapy 
at Stage 1. Then, depending on 
the results, the combination 
could be further evaluated in 
Stage 2 and beyond, if pre-
established GO criteria is met 


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21 5.1.3  
Added: In “Part B dose-expansion and” Part C, ... 
 
“Clinical site must provide documentation of tumor PD-L1 expression and EGFR mutation 
and/or ALK translocation status as evaluated by FDA-approved tests in Part B and Part C 
patients.  Participation in both parts will be dependent upon supplying tumor tissue (from 
fresh biopsy or archival) from a location that has not been radiated. Formalin-fixed specimens 
obtained either at the time of or after the diagnosis of metastatic disease will be required for 
performance of sequencing analysis. In Part C, biopsies obtained PRIOR to receipt of 
neoadjuvant/adjuvant chemotherapy are NOT permitted. Only subjects whose tumors express 
PD-L1 (TPS ≥1%) as determined by as determined by an FDA-approved test, will be eligible 
for enrollment in Part C. Furthermore, documentation of EGFR mutation and/or ALK 
translocation status will be required for subjects with non-squamous NSCLC. If the clinical 
site is unable to provide this source documentation, PD-L1 expression and EGFR/ALK testing 
should be performed in all Part C patients per institutional standard of care using FDA-
approved tests before enrollment. See Section 9.5. 
Clarification and addition of 
correlative work 
 
PD-L1 expression with FDA-
approved tests can now be 
conducted at local laboratory 
facilities as it is standard of care. 
No need for central lab testing  
 
PD-L1 expression in baseline 
tumor samples changed from 
≥50% to Tumor Proportion 
Score (TPS) ≥1% as determined 
by an FDA-approved test 
22 5.2.2 
Part B dose-expansion: Added rationale for design 
Clarification 
23 5.2.3 
Deleted rationale for priming in Part C 
No need for priming with 
ADXS-503 1st before addition of 
pembro based on results from 
Part B  
24 5.3 
Increased number of subjects enrolled 
Part B expansion following a 
Simon’s Two-stage design  
25 7.1.2/ 
7.1.3 
Part C: Starting at Week 1 (±2 days), ADXS-503 and pembrolizumab will be administered on 
the same day 
Not necessary to prime with 
ADXS-503 (see 18 above) 
 


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26 7.1.2/ 
7.1.3 
Part B and Part C Infusion of ADXS-503 can be through the infusion line used for 
pembrolizumab. 
A single infusion line can be used for pembrolizumab and ADXS-503. Language added in 
Section 7.1.2. “For enrolled patients with difficulty to access veins, one infusion line for 
pembrolizumab may be used provided it is flushed after the pembrolizumab infusion, at pre-
infusion and post-infusion of ADXS-503 regimen. If the infusion line is the same, the in-line 
filter used for the infusion of pembrolizumab must be removed before infusing ADXS-503”. 
 
The central port or central venous catheter can be used to withdraw blood for correlative 
analysis. 
 
There is no reason to have 2 
independent IV lines for drug 
infusion every 3 weeks. The 
risks of an intravenous catheter 
include pain, bruising, clotting, 
bleeding, leakage of drug 
solution, and possibly infection 
at the catheter site can be 
prevented for patients with vein 
access difficulty. And patients in 
Part B can be with disease 
control on therapy for over a 
year, which prompts the 
clinicians to preserve IV access 
as much as possible. 
27 Trial Summary/2.2/ 
5.1/5.1.3/7.1.2 
Dosing scheme for Part B and Part C: Upon Investigator assessment and discretion, the 
schedule of therapy with 1x108 CFU of ADXS-503 + 200 mg of pembrolizumab, IV, could 
shift from every 3 weeks to every 6 weeks after the first year of study treatment. 
 
The use of pembrolizumab Q6W 
has been approved by FDA in 
the US. Current data in this 
study has shown that memory T 
cells are activated around week 
8 of combination therapy with 
ADXS-503 and pembrolizumab 
and that they persist at week 25 
on therapy. Hence, we assume 
that T cell activation with the 
combo in the first year of 
therapy Q3W will be enough to 
keep immunogenicity if we 
reduce the frequency of 
administration of the two drugs 
during the second year.  
28 7.7.1/6.2 
9.2.1.3/9.2.1.3.1.1 
9.2.1.3.1.2 
Added erythromycin and fluoroquinolones as an alternative antibiotic treatments in subjects 
with known intolerance and/or allergy to Bactrim and ampicillin. The exclusion criteria has 
been modified accordingly.  
 
Refer to IB Section 4.2.1; based 
on documenting dual 
hypersensitivity to ampicilin and 
TMP/SMZ and the activity of 
other antibiotics with anti-
Listeria effect. 


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29 6.2 Exclusion Criteria  
#13 
Hernia mesh, and some metal plates are now listed under more common devices permitted. 
To provide flexibility at 
enrollment without 
compromising safety 
30 2.1, 9.4.2 
Added: “•During the Lm surveillance Follow-up Period, subjects will be contacted remotely 
every 3 months (±2 week) for 1 year to determine whether they have experienced for several 
days, the following symptoms that could potentially be associated with delayed listeremia and 
require prompt attention at the research site: fever or chills, headache, nausea, confusion or 
changes in alertness (for over 72 hours). As part of EOT procedures, upon completing the Lm 
Surveillance period, site staff should instruct subjects to contact the site if they experience any 
of these symptoms, as applicable. 
 
Clarification that the follow-up 
period will also include Lm 
monitoring to continue 
assessments for potential 
listeremia during the telephone 
calls or text messages or an app 
inquiring survival status, in 
addition to instructions provided 
to patients following the 1-year 
follow-up period.   
To provide instructions for Lm 
surveillance (LmS) monitoring 
addressing FDA request 
(emailed August 10, 2018).  
This for Lm surveillance 
strategy is consistent with the 
agreement between FDA and 
Advaxis of a 1-year LmS being 
sufficient, per the FDA written 
responses (dated 10 November 
2020) to the questions in a Type 
C Meeting (meeting information 
package submitted in SN0177 to 
IND 13,712). 
31 10.1 
Added sample size calculation for Part B dose-expansion: 
The sample size in Part B dose-expansion at dose level 1 (DL-1) will use Simon's optimal 
Two-stage design (Simon, 1989). The Part B dose-expansion will be carried out in 2 stages. In 
stage I, a total number of 18 subjects is accrued. If there are 2 or fewer responses among these 
18 patients, the study will be stopped early. Otherwise, an additional 25 patients will be 
accrued in stage II, resulting in a total sample size of 43 subjects. If there are 8 or more 
responses among these 43 subjects, we reject the null hypothesis and claim that the treatment 
is promising. The design controls the type I error rate at 0.05 and yields a power of 0.8. 
 
Part B expansion following a 
Simon’s Two-stage design 
based on a target response rate 
of 25% 


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r1 
n1 
r 
n 
Type I error 
Power PET(p0) EN(p0) 
Optimal 2 
18 
7 
43 
0.48 
0.8003 0.7338 24.7 
Note: r1 = the first stage threshold to stop the trial for futility; n1 = number of accrual subjects for stage 
I; n = total number of subjects; r = overall threshold to stop the trial for futility; EN(p0) = expected 
sample size for the cohort when the true response rate is p0; PET(p0) = probability of early termination 
when the true response rate is p0. 
32 Appendix 4 
Added: “Any SAE that occurs within the follow-up period, that is associated with a case of 
confirmed delayed listeremia during this Lm surveillance study, once becoming aware of any 
blood culture that is positive for Lm during the Lm surveillance monitoring period, must be 
reported within 24 hours to the Sponsor, so that the Sponsor can promptly send a notification 
via email and/or voicemail to both FDA and Centers for Disease Control and Prevention 
(CDC) concurrently, whether or not it fulfills expedited reporting requirements.” 
Increased SAE monitoring 
during Lm Surveillance 
 
 


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14. 
Appendices 
 
 


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Appendix 1 Abbreviations and Terms 
AE 
Adverse event 
ALK 
Anaplastic lymphoma kinase  
ALT/SGPT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APC 
Antigen presenting cell 
aPTT 
Activated partial thromboplastin time 
AST/SGOT 
Aspartate transaminase 
β-HCG 
Beta human chorionic gonadotropin 
BRAF 
 B-Raf proto-oncogene 
BCG 
Bacillus Calmette–Guérin vaccine 
BSL-2 
Biosafety level 2 
BOR 
Best overall response 
C 
Degrees Celsius 
CBC 
Complete blood count 
cfDNA 
Cell free DNA 
CFU 
Colony forming units 
cHL 
chronic Hodgkin lymphoma 
CMP 
Complete Metabolic Panel 
CNS 
Central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
Creatine phosphokinase 
CR 
Complete response 
eCRF 
Electronic case report form 
CrCl 
Creatinine clearance 
CRP 
C-Reactive Protein 
CRS 
Cytokine release syndrome 
CSR 
Clinical study report 
CT 
Computed tomography 


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CTA 
Cancer testis antigen 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte-associated protein 4 
DAMP 
Damage-associated molecular pattern 
DCR 
Disease control rate 
DL 
Dose level 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of objective tumor response 
DS 
Double strength 
EBUS 
Endobronchial ultrasound 
ECOG 
Eastern Cooperative Oncology Group 
ESI 
Events of special interest 
EGFR 
Epidermal growth factor receptor 
ESR 
Erythrocyte Sedimentation Rate 
FDA 
US Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl-transferase 
HBsAg 
Hepatitis B virus surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HPV 
Human papillomavirus 
HR 
Hazard ratio 
HRT 
Hormone replacement therapy 
HSCT 
Hematopoietic stem cell transplant 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 


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Protocol ADXS-503-101 
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ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFNγ 
Interferon gamma 
IHC 
Immunohistochemistry 
IL 
Interleukin 
ILD 
Interstitial lung disease 
INR 
International normalized ratio 
ir 
Immune-related 
IRB 
Institutional Review Board 
iBOR 
Immune best overall response 
iCR 
Immune complete response 
iUPD 
Immune unconfirmed progressive disease 
iCPD 
Immune confirmed progressive disease 
iPR 
Immune partial response 
iRC 
Immune response criteria 
iRECIST 
Immune Response Evaluation Criteria in Solid Tumors 
iSD 
Immune stable disease 
IV 
Intravenous 
KM 
Kaplan-Meier 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
LDH 
Lactate dehydrogenase 
LLO 
Listeriolysin O 
Lm 
Listeria monocytogenes 
LmS  
Lm surveillance 
MAb 
Monoclonal antibody 
MAD 
Maximum administered dose 
mCRPC 
Metastatic castrate-resistant prostate cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDSC 
Myeloid-derived suppressor cells 
MHC 
Major histocompatibility complex 


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MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NOAEL 
No-observed-adverse-effect-level 
NSAID 
Non-steroidal anti-inflammatory drug 
NSCLC 
Non-small cell lung cancer 
OFA 
Oncofetal antigen 
ORR 
Objective response rate 
OS 
Overall survival 
PAMP 
Pathogen-associated molecular pattern 
PBMC 
Peripheral blood mononuclear cell 
PBS 
Phosphate buffered saline 
PD 
Progressive disease 
PD-1 
Programmed death receptor-1 
PD-L1/ PD-L2 
Programmed death-ligand 1 / Programmed death-ligand 2 
PFS 
Progression-free survival 
PI3K 
Phosphoinositide 3-kinase 
PK 
Pharmacokinetic 
PR 
Partial response 
prn 
pro re nata; when necessary 
PT 
Prothrombin time 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROS1 
ROS proto-oncogene-1 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAER 
Serious adverse event report 
SAP 
Statistical Analysis Plan 
SCID 
Severe combined immune deficiency 
SCLC 
Small cell lung cancer 
SD 
Stable disease 


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SoA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
SumD 
Sum of longest diameters 
T1DM 
Type 1 diabetes mellitus 
t1/2 
Elimination half-life 
TA 
Tumor assessment 
TAA 
Tumor associated antigen 
TCR 
T cell receptor 
TSH 
Thyroid stimulating hormone 
TKI 
Tyrosine kinase inhibitor 
TME 
Tumor microenvironment  
TRAE 
Treatment-related adverse event 
tLLO 
Truncated Listeriolysin O 
TMTB 
Total measurable tumor burden 
TNF 
Tumor necrosis factor 
TPS 
Tumor Proportion Score 
Tregs 
Regulatory T cells 
ULN 
Upper limit of normal 
US, USA 
United States of America 
USP 
United State Pharmacopeia 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell count 
WHO 
World Health Organization 
WOCBP 
Women of Child-Bearing Potential 
 
 
 
 


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Appendix 2 Clinical Laboratory Tests 
• The tests detailed in Table 2.1 and Table 2.2 will be performed by the local laboratory 
• Laboratory values for subject inclusion in the study are detailed in Table 2.1 
• Safety laboratory assessments to be performed during the study are detailed in Table 2.2 
• Additional tests may be performed at any time during the study as deemed necessary by 
the Investigator or Sponsor or required by local regulations 
• Investigators must document their review of each laboratory report. 
Table 2.1: Organ Function Requirements for Study Inclusion 
System 
Laboratory Value 
Hematologic 
Absolute neutrophil count (ANC) a 
≥1 x 109/L (Parts A and B); ≥1.5 x 109/L (Part C) 
Platelets a 
≥75 x 109/L (Parts A and B); ≥100 x 109/L (Part C) 
Hemoglobin a 
≥9 g/dL or ≥ 5.6 mmol/L 
WBC a 
≥2000/ µL 
Renal 
Serum creatinine OR 
Measured or calculated creatinine clearance 
(CrCl). Note: GFR can also be used in place of 
serum creatinine or CrCl 
≤1.5 x upper limit of normal (ULN) OR 
 
≥50 mL/min for subjects with serum creatinine levels >1.5 
x institutional ULN b 
Hepatic 
Serum total bilirubin 
≤1.5 x ULN (except subjects with Gilbert Syndrome, who 
must have total bilirubin <3 x ULN) 
AST (SGOT) and ALT (SGPT) 
<3 x ULN (Parts A and B); <1.5 x ULN (Part C) 
Endocrine 
Thyroid stimulating hormone (TSH) 
Within normal limits (Parts B and C only). c 
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 
aANC, platelets, hemoglobin, or WBC requirement cannot be met by the use of recent transfusions, or growth factor 
support (G-CSF, erythropoietin, etc.) within 2 weeks prior to treatment initiation.  
bCreatinine clearance should be calculated per institutional standard. 
cIf TSH is not within normal limits, subject may still be eligible if T3 and free T4 are within normal limits.  


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Table 2.2: Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
Mean Corpuscular 
Volume (MCV) 
Mean Corpuscular 
Hemoglobin (MCH) 
% Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Absolute Neutrophil 
Count (ANC) 
Red Blood Count (RBC)  
Hemoglobin 
Hematocrit 
Clinical 
Chemistry 
Blood Urea 
Nitrogen (BUN) 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT) 
Total bilirubin and 
direct bilirubin (if 
total bilirubin is 
elevated above the 
upper limit of normal) 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT) 
Total Protein 
 
Glucose 
Calcium 
Alkaline phosphatase 
Lactate dehydrogenase 
(LDH) 
 
Carbon dioxide 
(CO2 or 
bicarbonate) 
Chloride 
 
 
Routine 
Urinalysis 
• Specific gravity 
• Glucose, protein, blood 
• Microscopic examination (if blood or protein is abnormal) 
Other Tests 
• Follicle-stimulating hormone and estradiol (as needed for WOCBP only) 
• Urine (confirmed by serum if urine is positive) human chorionic gonadotropin 
(βHCG) pregnancy test (as needed for WOCBP only) 
• Coagulation profile (PT/INR and aPTT) is required only at Screening and 
subsequently as clinically indicated 
• Part B and Part C: Total Triiodothyronine (T3) or Free T3 (FT3); Free T4, 
Thyroid stimulating hormone (TSH) 
Lm blood 
culture: 
• A blood sample will be collected at 7 days (±3 days) after completion of the 3-
week course of oral antibiotics to culture for Lm. 
The results of each test must be entered into the eCRF. 
 
 


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Appendix 3 Study Governance Considerations 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
• The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC 
o Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures 
o Overall conduct of the study at the site and adherence to requirements of 21 CFR, 
ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability 
Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 


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• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
If participants will be asked to consent to optional exploratory research using the remainder of 
mandatory samples, include text that addresses the use of remaining mandatory samples for 
optional exploratory research. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. Participants will be told that they are free 
to refuse to participate and may withdraw their specimens at any time and for any reason during 
the storage period. A separate signature will be required to document a participant's agreement to 
allow any remaining specimens to be used for exploratory research. Subjects who decline to 
participate in optional exploratory research will not provide this separate signature. 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.  
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
Dissemination of Clinical Study Data 
This study will be registered and results posted on www.clinicaltrials.gov. The sponsor has 
proprietary interest in the study. Authorship and manuscript composition will reflect joint 


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cooperation between study investigator(s) and sponsor personnel. Authorship will be established 
prior to the writing of the manuscript. As this study may be multicenter, no individual 
publication will be allowed prior to completion of the final report of the multicenter study, 
except as agreed with the sponsor. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator after study completion for the maximum period 
required by applicable regulations and guidelines, institution procedures, or the period 
specified by the sponsor, whichever is longer. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
Study and Site Closure 
The sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.


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Appendix 4 Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, radiological scans, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the Investigator (ie, not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the Investigator to be 
more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
 
 
 


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Events Meeting the ESI Definition for this Trial 
• Signs and symptoms during or after treatment infusion: Any of the following 
events, if they were considered to be treatment-related and began within 24 hours 
after study treatment, and were ≥Grade 3: hypotension, hypoxia, encephalopathy 
or organ toxicity.  
• Immune-related adverse events (irAE): ≥Grade 3 treatment-induced events (acute, 
sub-acute or late occurring) that involve inflammatory reactions that were 
mediated through the action of T cells on the subject’s tissues or organs. 
• Delayed listeremia: The presence of Lm in a blood culture after treatment with 
ADXS-503. Once becoming aware of any blood culture that is positive for Lm 
during the Lm surveillance monitoring period, the Sponsor must be notified 
within 24 hours so that the Sponsor can promptly send a notification via email 
and/or voicemail to both FDA and Centers for Disease Control and Prevention 
(CDC) concurrently, whether or not it fulfills expedited reporting requirements. 
Additional testing may be performed by CDC to evaluate the bacteria for the 
presence of genetic elements that are consistent with an Lm-based immunotherapy 
drug. NOTE: this does not include the presence of Lm in a blood culture 
within the first 48 hours after treatment with ADXS-503.  
Reporting of ESI will begin from the date of first dose of study treatment must be reported 
within 24 hours of awareness to the sponsor appointed Pharmacovigilance service provider. ESIs 
will be reviewed in order to identify notable safety trends. In Part A and Part B, ESI will be 
reviewed as they are reported and will be discussed at the time of the dose escalation meetings, 
and periodically afterwards. In Part C, ESI will be reviewed and discussed on an ongoing basis.  
Definition of SAE 
Any SAE, or follow-up to an SAE, including death due to any cause, that occurs to any 
participant within 24 hours of receipt of the information from the time the Informed Consent 
Form is signed through 30 days following cessation of treatment, or the initiation of a new anti-
cancer therapy, whichever is earlier, whether or not related to study product, must be reported 
within 24 hours to the EDC tool. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 


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would not have been appropriate in the physician’s office or outpatient setting. Complications 
that occur during hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other seriousness criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. 
Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial and persistent disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or 
may require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious. 
Examples of such events include intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
Recording AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to the 
event. 
• 
The Investigator will then record all relevant AE/SAE information in the eCRF. 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be blinded on the copies of the medical records before submission 
to the Sponsor. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 


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Considerations for reporting treatment-related toxicity 
• 
Investigators must use their best judgement to appropriately code and treat individual 
AEs that occur during or after treatment infusion.  In particular, it’s important to 
record individual components of AEs that occur on the day of dosing. Instead of 
grouping signs and symptoms into broad categories, such as “infusion reaction” or 
“cytokine release syndrome”, each term must be reported as a verbatim AE term 
with an assessment of severity, seriousness, and relationship to study treatment.  This 
reporting is important, because it provides essential information regarding the nature 
of observed toxicity, and facilitates the application of appropriate and specific 
management strategies. 
 
Assessment of Intensity 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE 
v4.03) will be used to evaluate AEs and SAEs.  
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on this general guideline: 
 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*. 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
 
A Semi-colon indicates ‘or’ within the description of the grade. 
A single dash (-) indicates a grade is not available. 
Activities of Daily Living (ADL) 
 *Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc.  
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study treatment and each 
occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. 


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• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated. 
• 
The Investigator will also consult the IB/ Product Label (if applicable) in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the EDC tool. However, it is very important 
that the Investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the EDC tool. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of AE and SAE 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor 
appointed Pharmacovigilance provider to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide a certificate of death, if available. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to the EDC tool within 24 hours of 
receipt of the information from the time the consent/assent is signed through 30 days after 
the last dose of study treatment, regardless of relatedness.  
Reporting of SAE to the Sponsor or Designee 
SAE Reporting to Sponsor 
• 
If a site receives a report of a new SAE from a study participant or receives updated data on 
a previously reported SAE, the site can report this information to the sponsor appointed 
Pharmacovigilance service provider.  Detailed instructions for such reporting will be 
provided separately to sites.  
• 
Adverse reactions will be reported to FDA according to 21 CFR 312.32. 
 


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Appendix 5 Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered WOCBP 
1. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s: (1) review of participant’s 
medical records; (2) medical examination; or (3) medical history interview. 
2. Premenarchal 
 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.  
 
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance 
• Male participants with female partners of child-bearing potential are eligible to 
participate in this study if they agree to use a highly effective method of contraception 
during the treatment period and for at least 120 days after the last dose of study 
treatment. 
 
• Women of childbearing potential are eligible to participate in this study if they agree to 
use 2 highly effective methods of contraception consistently and correctly as described 
in the table below. 
 


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Highly Effective Contraceptive Methods That Are User Dependent b 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulation 
• 
oral 
• 
intravaginal 
• 
transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
oral 
• 
injectable 
Highly Effective Methods That Are User Independent b 
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.  
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant.  
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for clinical study 
participants.  
b) Two highly effective methods of contraception should be utilized during the treatment period and for 
at least 120 days after the last dose of study treatment.  
 
Pregnancy Testing 
• WOCBP will only be included in the study after a negative highly sensitive pregnancy test. 
• Additional pregnancy testing should be performed as described in the SoA and as required 
locally. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required. 
• Pregnancy testing, with a minimum sensitivity of 25 IU/L or equivalent units of βHCG will 
be performed locally. 
Collection of Pregnancy and Lactation Information 
• The Investigator will collect pregnancy/lactation information on any female participant or 
female partner of a male participant who becomes pregnant or breastfeeds while 
participating in this study and for at least 120 days after the last dose of study treatment. 


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• Information will be recorded on the appropriate form and submitted to the Sponsor 
appointed Pharmacovigilance provider within 24 hours of learning of a participant's 
pregnancy or lactation case. 
• The pregnancy will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and neonate, which will be 
forwarded to the Sponsor appointed Pharmacovigilance provider. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. 
• Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 
• While pregnancy and lactation itself are not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. 
• A spontaneous abortion is always considered to be an SAE and will be reported as such. 
• Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the Investigator, will be reported to the EDC tool as 
described in Appendix 4. While the Investigator is not obligated to actively seek this 
information in former study participants, he/she may learn of an SAE through spontaneous 
reporting. 
Any female participant who becomes pregnant or breastfeeds while participating in this study 
will discontinue study treatment. 


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Appendix 6 Recommended Management Guidelines for Infusion Reactions  
NCI CTCAE v4.03 Grade 
Management 
Grade 1 
 
Mild transient 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 
 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for ≤24 hrs. 
1. 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is not limited to: 
 
IV fluids 
 
Antihistamines 
 
NSAIDS 
 
Acetaminophen 
 
Narcotics 
2. 
Increase monitoring of vital signs as medically indicated until the subject is 
deemed medically stable in the opinion of the Investigator. 
 
If symptoms resolve within one hour of stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate. Otherwise dosing will be held until 
symptoms resolve and the subject should be pre-medicated for the next scheduled dose. 
ADXS-503-Related: continue with protocol-described pre-medication for next infusion. 
Pembrolizumab-Related: Subject may be pre-medicated 1.5 h (+/- 30 mins) prior to the 
next infusion with: 
• 
Diphenhydramine 50 mg orally (or equivalent dose of antihistamine) 
• 
Acetaminophen 500-1000 mg orally (or equivalent dose of antipyretic) 
If despite adequate pre-medication the subject developments recurrent Grade 2 infusion-
related toxicity that is considered by the Investigator to be related to pembrolizumab, the 
subject should be permanently discontinued from pembrolizumab treatment. 
 
Grade 3  
 
Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae. 
 
 
 
 
 
 
 
1. 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
2. 
Increase monitoring of vital signs as medically indicated until the subject is 
deemed medically stable in the opinion of the Investigator.  
3. 
Hospitalization may be indicated.   
ADXS-503-Related: Subjects who experience a Grade 3 infusion-related toxicity that is 
considered by the Investigator to be related to ADXS-503, may be discontinued from 
study treatment. Discussion with the Sponsor is recommended. 
Pembrolizumab-Related: Subjects who experience a Grade 3 infusion-related  toxicity 
that is considered by the Investigator to be related to pembrolizumab, should be 
permanently discontinued from pembrolizumab treatment. 
Grade 4 
Life-threatening consequences; urgent intervention 
indicated. 
 
Subjects who experience a Grade 4 infusion reaction should be permanently discontinued 
from study treatment.  
Follow institutional standard of care. 
Sponsor should be contacted. 
 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug administration. 


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Appendix 7 Grading and Management Guidelines for Acute Hypotension, Hypoxia, Encephalopathy, 
Organ Toxicity, Fever and Constitutional Symptoms 
The grading scale and toxicity management criteria below are adapted from criteria proposed by MD Anderson Cancer Center:  Chimeric Antigen Receptor 
(CAR) Cell Therapy Toxicity Assessment and Management - Adult  (10/31/2017) 
Table 7.1. Grading Scale for Hypoxia, Hypotension, and Organ Toxicity 
Grade 
Description of Severity 
1 
Fever (temperature > 38○C) or Grade 1 organ toxicity 
2 
Symptoms require and respond to moderate intervention 
Oxygen requirement FiO2 < 40%, and/or subject requires intermittent supplemental oxygen,  
              OR 
Hypotension responsive to IV fluids or low-dose of one vasopressor to maintain systolic blood pressure > 90 mmHg,  
 
OR 
Grade 2 organ toxicity  
3 
Needs oxygen to maintain O2 saturation > 90% Oxygen requirement FiO2 ≥ 40% and/or requiring BiPAP,  
 
OR 
Hypotension refractory to management for Grade 2 or where hospitalization is required,  
 
OR 
Grade 3 organ toxicity or Grade 4 transaminitis per CTCAE v4.03 criteria 
4 
Life-threatening signs and symptoms 
 
OR 
Requirement for ventilator support to maintain O2 saturation > 90%   
 
OR 
Grade 4 organ toxicity (excluding Grade 4 transaminitis) per CTCAE v4.03 criteria 


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Table 7.2. Management Guidelines for Acute Hypotension, Hypoxia, Organ Toxicity, Fever and 
Constitutional Symptoms 
 
Toxicity 
Grade 
Sign/Symptom 
Treatment 
Instructions for Interruption 
of ADXS-503  
Modification for 
Subsequent infusions 
1 
Hypotension 
• Supportive care 
Not applicable 
• Increase pretreatment 
IV fluids (eg, 500 ml 
-1L normal saline) 
1 
Fever; 
Constitutional symptoms; 
Grade 1 organ toxicity 
• Symptomatic management of 
constitutional symptoms and organ 
toxicity 
• Acetaminophen and hypothermia 
blanket as needed for fever 
• Ibuprofen if fever is not controlled 
with above, use with caution or 
avoid if thrombocytopenic 
• IV fluids as needed 
• Consider the IL-6 antagonist 
tocilizumab for persistent (>3 days) 
or refractory fever 
 
 
 
 
 
 
 
Not applicable 
• No modification 


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Toxicity 
Grade 
Sign/Symptom 
Treatment 
Instructions for Interruption 
of ADXS-503  
Modification for 
Subsequent infusions 
 
2 
 
Hypotension 
• Fluids (500 – 1000 mL normal 
saline to keep systolic blood 
pressure > 90 mmHg)  
• If hypotension persists despite IV 
fluid bolus and a low dose pressor, 
administer the IL-6 antagonist 
tocilizumab (8 mg/kg IV over 1 
hour)  
• If hypotension persists after IV fluid 
bolus, administer a vasopressor (eg, 
epinephrine 0.5 mg IM), and 
consider transfer to ICU  
• If hypotension persists despite these 
measures, treat with a high-dose 
corticosteroid.  
•  If there are signs of hypo-perfusion 
or if there is rapid deterioration in 
the opinion of the clinician, may use 
dexamethasone 10 mg IV every 6 
hours 
• Increase frequency of monitoring 
vital signs 
 
 
 
 
 
 
• Immediately interrupt 
ADXS-503 until AE(s) 
resolve to Grade ≤ 1 but for 
no less than 72 hours 
 
• Permanently discontinue 
ADXS-503 if there is no 
improvement of AE(s) to ≤ 
Grade 1 within 7 days. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Extend infusion time 
to 2 hours  
• Increase pretreatment 
IV fluids (eg, 500 mL 
– 1L normal saline)  
• Incorporate 
Glucocorticoid- 
Hydrocortisone or 
equivalent- 50 mg, 
IV, as premedication 
 
2 
Hypoxia 
• Use supplemental oxygen as needed 
• No modifications 


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Toxicity 
Grade 
Sign/Symptom 
Treatment 
Instructions for Interruption 
of ADXS-503  
Modification for 
Subsequent infusions 
 
 
 
 
 
 
 
 
• Use tocilizumab 8 mg/kg IV with or 
without corticosteroids as with 
Grade 2 hypotension (described 
above) 
• Increase frequency of monitoring 
vital signs 
• Restrict the administration of IV 
fluid if possible 
See above 
• Discussion with 
Sponsor 
recommended 
2 
 
 
 
 
 
 
 
 
Fever, 
Constitutional symptoms; 
Grade 2 organ toxicity 
 
 
 
 
 
 
• Appropriate supportive care 
• Manage organ toxicity as per 
standard guidelines 
• Use tocilizumab 8 mg/kg IV with or 
without corticosteroids as described 
above for Grade 2 hypotension 
• Manage fever and constitutional 
symptoms as noted above for Grade 
1 toxicity 
 
 
 
 
 
 
 
 
• Extend infusion time 
to 2 hours  
• Consider increasing 
doses of prophylactic 
medications 
• Discussion with 
Sponsor 
recommended, but 
not required 
3 
 
Hypotension  
 
• IV fluid bolus (as for Grade 2 
hypotension) and tocilizumab 
(8mg/kg IV over 1 hour) 
• Immediately interrupt 
ADXS-503  
• Discuss with Sponsor 


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Toxicity 
Grade 
Sign/Symptom 
Treatment 
Instructions for Interruption 
of ADXS-503  
Modification for 
Subsequent infusions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
o If an IV fluid bolus was 
previously administered it may 
be repeated, depending on the 
subject’s hemodynamic status.  
However, IV fluid 
administration in the presence of 
hypoxia may lead to increased 
pulmonary edema (see guidance 
for hypoxia above) 
o Tocilizumab IV may not be 
administered if it was used 
within the previous 8 hours 
• Transfer subject for inpatient 
management 
• High dose vasopressors (eg, 
Dopamine 10 µg/kg/min)   
• If hypotension worsens or is 
unresponsive to above measures, 
administer high dose corticosteroids 
(methylprednisolone or 
dexamethasone)  
• Monitor for neurologic signs and 
symptoms.  Consult neurology to 
assess for signs of elevated 
intracranial pressure (eg, 
papilledema) /cerebral involvement. 
See Tables 7.3 and 7.4 below for 
grading and management of 
encephalopathy  
• Increase frequency of monitoring 
vital signs 
• Permanently discontinue 
ADXS-503 if there is no 
improvement in AE(s) to ≤ 
Grade 2 within 5 days or 
AE ≤ Grade 1 within 7 days 
 
 
 
 


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Toxicity 
Grade 
Sign/Symptom 
Treatment 
Instructions for Interruption 
of ADXS-503  
Modification for 
Subsequent infusions 
3 
Hypoxia 
• Use supplemental oxygen  
• Use tocilizumab 8 mg/kg IV with or 
without corticosteroids as in 
hypotension 
• Increase frequency of monitoring 
vital signs 
• Restrict the administration of IV 
fluid if possible 
• Immediately interrupt 
ADXS-503  
 
• Discuss with Sponsor 
3 
Fever, 
Constitutional symptoms; 
Grade 3 organ toxicity 
 
• Appropriate supportive care 
• Manage organ toxicity as per 
standard guidelines 
• Use tocilizumab 8 mg/kg IV, 
corticosteroids  
• Manage fever and constitutional 
symptoms above for Grade 1 
toxicity 
• Immediately interrupt 
ADXS-503  
 
• Discuss with Sponsor 
4 
Hypotension 
• IV fluid bolus (as for Grade 2 
hypotension) and tocilizumab  
• High-dose methylprednisolone 
• Immediately interrupt 
ADXS-503  
 
• Permanently 
discontinue ADXS-
503 
4 
Hypoxia 
• Mechanical ventilation 
• Tocilizumab, high-dose 
methylprednisolone, and supportive 
care 
• Immediately interrupt 
ADXS-503  
 
• Permanently 
discontinue ADXS-
503 
4 
Fever, 
Constitutional symptoms; 
Grade 4 organ toxicity 
• Appropriate supportive care 
• Manage organ toxicity as per 
standard guidelines 
• Immediately interrupt 
ADXS-503  
 
• Permanently 
discontinue ADXS-
503 


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Toxicity 
Grade 
Sign/Symptom 
Treatment 
Instructions for Interruption 
of ADXS-503  
Modification for 
Subsequent infusions 
 
• Tocilizumab, high-dose 
methylprednisolone, and supportive 
care  
• Manage fever and constitutional 
symptoms as noted for Grade 1 
above 
• Increase frequency of monitoring 
vital signs 
 
* Tocilizumab is a humanized, immunoglobulin G1k (IgG1k) anti-human IL-6R mAb approved for treatment of adult patients with moderately to severely active 
rheumatoid arthritis (RA) who have had an inadequate response to Disease-Modifying Anti-Rheumatic Drugs (DMARDs), for the treatment of active 
polyarticular juvenile idiopathic arthritis (PJIA), and active systemic juvenile idiopathic arthritis (SJIA) in patients 2 years of age and older, and for the treatment 
of adults and pediatric patients 2 years of age and older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release 
syndrome.  
 
Tocilizumab works by preventing IL-6 binding to both cell-associated and soluble IL-6 receptors (Actemra®, 2020; Grupp 2013; Lee 
2014; Winkler 1999). 
 
Dosing guidelines for tocilizumab are provided below. 
 
Tocilizumab Dosing Guidelines (Actemra®, 2020) 
 
• 8 mg/kg IV; maximum dose/infusion = 800 mg. 
 
• If the subject’s condition does not improve or stabilize within 8 hours of the tocilizumab dose, administration of a second dose 
of tocilizumab should be considered.  A total of three doses can be administered in a 24-hour period (maximum 800 mg/dose), 
and a maximum of 4 doses total can be administered. 
 
• Tocilizumab may be administered with corticosteroids. 


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Table 7.3. Grading Scale for Encephalopathy 
Grade 
Description of Severity 
1 
Neurological assessment score (see below) – Mild (7-9) 
2 
 Neurological assessment score (see below) – Moderate (3-6) 
3 
Neurological assessment score (see below) - Severe (0-2) 
OR 
Stage 1 or 2 papilledema1 with CSF opening pressure less than 20 mmHg 
4 
Neurological assessment score Critical / obtunded 
OR 
Stage 3, 4, or 5 papilledema1 or CSF opening pressure greater than or equal to 20 mmHg or cerebral edema 
CARTOX 10-point neurological assessment (Assign one point for each task performed correctly; score of 10 = normal) 
● Orientation to year, month, city, hospital, President: 5 points 
● Name 3 objects (point to clock, pen, button): 3 points  
● Ability to write a standard sentence (eg, Our national bird is the bald eagle): 1 point 
● Count backwards from 100 by ten: 1 point 
1 Papilledema grading is performed according to Modified Frisén scale 
CSF = cerebrospinal fluid 
 


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Table 7.4. Management Guidelines for Encephalopathy 
 
Toxicity Grade 
Treatment 
Instructions for 
Interruption of ADXS-503 
Modification for 
Subsequent Infusions 
1 
● Vigilant supportive care; aspiration precautions; IV 
hydration 
● Withhold oral intake of food/medicines/fluids and assess 
swallowing  
● Convert all oral medications and/or nutrition to IV if 
swallowing is impaired         
● Avoid medications that cause CNS depression     
● Low doses of lorazepam (0.25-0.5 mg IV every 8 hours) 
or haloperidol (0.5 mg IV every 6 hours) may be used for 
agitated patients with careful monitoring                       
Not applicable 
Discuss with Sponsor 
 
● Neurology consultation                                 
● Daily CARTOX 10-point neurological assessment as in 
Table 7.3                          
● Fundoscopic exam to assess for papilledema  
● MRI brain with and without contrast; diagnostic lumbar 
puncture with OP; MRI spine if focal signs exist; CT of 
brain may be performed if MRI brain is not feasible             
 
 
 
 
 
 


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Toxicity Grade 
Treatment 
Instructions for 
Interruption of ADXS-503 
Modification for 
Subsequent Infusions 
2 
● Supportive care and neurological workup as per Grade 1 
● IL-6 antagonist (tocilizumab1), if associated with other 
events such as refractory hypotension and/or hypoxia 
● Dexamethasone or methylprednisolone if refractory to 
tocilizumab1 therapy, when it is administered 
● Consider ICU transfer if associated with other events 
such as hypotension or hypoxia  
• Immediately interrupt 
ADXS-503  
 
Discuss with Sponsor 
3 
● Supportive care and neurological workup as per Grade 1 
● ICU transfer is recommended 
● Tocilizumab1, if associated with concurrent refractory 
hypotension and/or hypoxia and if not administered 
previously 
● Dexamethasone or methylprednisolone around the clock, 
if symptoms worsen despite tocilizumab therapy. Continue 
corticosteroids until improvement to Grade 1 and then taper 
or stop. 
● Low grade (Stage 1 or 2) papilledema with CSF OP less 
than 20 mmHg, acetazolamide as per Institutional 
guidelines 
● Consider repeat neuro-imaging (CT or MRI) every 2-3 
days if persistent event greater than or equal to Grade 3 
 
 
 
• Immediately interrupt 
ADXS-503 
• Permanently 
discontinue ADXS-
503  
Not applicable 
4 
● Supportive care and neurological workup as per Grade 1 
• Immediately interrupt 
Not applicable 


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Toxicity Grade 
Treatment 
Instructions for 
Interruption of ADXS-503 
Modification for 
Subsequent Infusions 
● ICU monitoring; consider mechanical ventilation for 
airway protection 
● Tocilizumab1 and repeat neuro-imaging as per Grade 3 
● High dose methylprednisolone 
● For high-grade (Stage 3, 4, or 5) papilledema, CSF OP 
greater than or equal to 20 mmHg, or cerebral edema, 
follow Institutional guidelines for high dose steroids, 
hyperventilation, hyperosmolar therapy, metabolic profile; 
CT scan daily. 
ADXS-503 
• Permanently 
discontinue ADXS-
503 
1 IL-6 antagonist (tocilizumab) administration- See Table 7.2 
 


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Appendix 8 General Approach for Managing Immune-Related Adverse 
Events Associated with ADXS-503 
Immune-
Related AE 
Withhold/Discontinue ADXS-
503? 
Supportive Care 
Grade 1 
• No action. 
• Provide symptomatic 
treatment. 
 
Grade 2 
• May withhold ADXS-503. 
• Consider topical or systemic 
corticosteroid in addition to 
appropriate symptomatic 
treatment. 
 
 
Grade 3 and 
Grade 4 
• Withhold ADXS-503. 
• Discontinue if unable to 
reduce corticosteroid dose 
to <10 mg per day 
prednisone equivalent 
within 12 weeks of toxicity. 
• Systemic corticosteroids are 
indicated in addition to 
appropriate symptomatic 
treatment. May utilize 1 to 
2 mg/kg prednisone or 
equivalent per day. 
• Steroid taper should be 
considered once symptoms 
improve to Grade 1 or less 
and tapered over at least 4 
weeks. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 9 Guidelines to Manage Immune-Related Adverse Events 
Associated with Pembrolizumab 
The following guidance is according to the Product Label (Keytruda®) for pembrolizumab and 
can be found on the Keytruda® website at https://www.keytruda.com/  
 


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Appendix 10 
Assessment of Disease 
Tumor response will be evaluated at the tumor imaging timepoints specified in the SoA. Tumor 
response will be evaluated by the Investigator (or designee) according to RECIST v1.1 as the basis 
for the primary analysis of tumor response-based endpoints (Eisenhauer, 2009). Exploratory 
analysis of tumor-response will be performed by the Sponsor (or designee) according to iRECIST 
(Seymour, 2017). See Section 9.4.1. 
Baseline Tumor Assessment 
The baseline tumor burden (unidimensionally measured or evaluable disease) will be assessed 
during the pre-treatment Screening evaluations. The Investigator will identify prospectively, the 
lesions to be followed in order to evaluate the subject’s response to therapy (see 
Target/Non-target Lesions). Baseline imaging areas will include the chest, abdomen, pelvis and 
any additional known sites of disease. Subjects with known CNS metastases and subjects with 
signs or symptoms suggestive of brain metastasis should be evaluated with imaging of the brain at 
baseline. 
Tumor Imaging 
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. 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. 
Target/Non-Target Lesions 
All measurable lesions, up to a maximum of 2 lesions per organ and up to 5 lesions 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 (lesions 
with the longest diameters) 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.  
One exception to the above escribed approach is related to pathological lymph nodes. Pathological 
lymph nodes are defined as measurable lesions and may be identified as target lesions if the 
criterion of a short axis of ≥15 mm by CT is met. Only the short axis of these nodes will contribute 
to the baseline sum. Nodes that have a short axis <10 mm are considered non-pathological and 
should not be recorded or followed. 
Measurable lesions other than the target lesions (including pathologic lymph nodes) 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 assessment timepoints as target lesions. 
Measurable and Non-Measurable Lesions and Disease 
Measurable lesions will be those that can be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 


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• 10 mm for lesions other than lymph nodes and assessed by CT/MRI scan - (CT/MRI scan 
slice thickness no greater than 5 mm) 
• 10 mm for lesions assessed clinically by caliper measurement (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
• 20 mm for lesions assessed by chest x-ray  
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in subsequent assessments, only 
the short axis will be measured and followed. 
Non-measurable lesions/disease will be all other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with a ≥10 mm but <15 mm short 
axis), as well as truly non-measurable lesions. Truly non-measurable lesions include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses identified by physical exam and not 
measurable by reproducible imaging techniques.  
Special Considerations Regarding Lesion Measurability 
Bone Lesions 
• Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable. 
Cystic Lesions 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
Lesions with Prior Local Treatment 
Tumor lesions situated in a previously irradiated area, or in an area subjected to locoregional 
therapy, are usually not considered measurable unless there has been demonstrated progression in 
the lesion. 
Response in Target Lesions (RECIST v1.1) 
At baseline, the sum of the longest diameters (SumD) of all target lesions (up to 2 lesions per 
organ, up to 5 lesions total) is measured.  At each subsequent tumor assessment, the response in 
target and new measurable lesions is defined as follows:  


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• 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. 
Response in Non-Target Lesions (RECIST v1.1) 
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 (<10 mm 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).  
 
Tumor-Response According to iRECIST 
For a description of tumor-response evaluation according to iRECIST, and the differences 
between iRECIST and RECIST v1.1, refer to:  
 
Seymour L, Bogaerts J, Perrone A, et al.  iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics. Lancet Oncol. 2017; 18:e143-52.75 
 


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Appendix 11 
ECOG Performance Status 
ECOG Performance Status 
Grade 
Status 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, eg, light housework, 
office work. 
2 
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 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
Reference: (Oken, 1982)