Window of Opportunity Trial of Neoadjuvant ADXS 11-001 Vaccination Prior to Robot -Assisted Resection of HPV-Positive Oropharyngeal Squamous Cell Carcinoma
Phase: PHASE2
Conditions: Head and Neck Cancer, Squamous Cell Carcinoma of the Head and Neck, HPV Positive Oropharyngeal Squamous Cell Carcinoma
Sponsor: Andrew Sikora

 
 
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WINDOW-OF OPPORTUNITY TRIAL OF NEOADJUVANT ADXS11-001 VACCINATION PRIOR TO 
TRANSORAL RESECTION OF HPV-POSITIVE OROPHARYNGEAL SQUAMOUS CELL CARCINOMA 
 
CLINICAL TRIAL PROTOCOL 
Version 11.2 (January 9, 2020) 
 
IND# 15688 
 
Study Chairperson 
Andrew Sikora, M.D., Ph.D1 
 
 
 
Study Institutions: 
(1) Baylor College of Medicine  
One Baylor Plaza, Houston, Texas 77030 
Center for Cell and Gene Therapy 
Dan L Duncan Comprehensive Cancer Center 
 
(2) ISMMS - Icahn School of Medicine at Mount Sinai  
One Gustave L Levy Place, New York, NY 10029 
(3) Arizona State University 
Tempe, AZ 85281 
 
 
 

 
 
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BCM Site Principal Investigator 
 
Anita Sabichi, M.D.1 
 
 
ISMMS Site Principal Investigator 
 
 
Brett Miles, MD2 
 
 
 
Protocol Team 
Clinical Collaborators: 
At ISMMS:  
Marshall Posner, M.D. 2 
Eric Genden, M.D. 2 
Marita Teng, M.D. 2 
Krzysztof Misiukiewicz, M.D. 2 
At BCM:  
Vlad Sandulache, M.D. ,Ph.D1 
Donald Donovan M.D.1 
Andrew Huang, M.D.1 
Nelson Liou, M.D. 1  
Jun Zhang, M.D. 1 
 
 
    
 
Scientific Collaborators: 
At ISMMS: 
Seunghee Kim-Schulze, PhD.2 
Michael Donovan, M.D. 2 
Nina Bhardwaj, M.D./PhD. 2 
Sacha Gnjatic, PhD. 2 
David Zhang, M.D./PhD. 2 
 
At ASU: 
Karen Anderson, MD/PhD3 
 
 
 
 
 
 
 
 
 

 
 
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1 OBJECTIVES 
This is an investigator-initiated prospective clinical study of patients with stage I-IV squamous cell 
carcinoma of the oropharynx (OPSCC) who are to undergo ablative transoral surgery. We 
propose to test the hypothesis that the Listeria-based HPV vaccine ADX11-001 induces 
circulating and tumor-infiltrating antigen-specific T cells in HPV16+ oropharyngeal cancer patients 
undergoing transoral resection. The results of this trial will assess the ability of ADX11-001 
vaccination to induce a robust HPV-specific cytotoxic lymphocyte (CTL) response in the blood 
and tumor. 
1.1  Primary Aims 
 
 
1.1.1 To determine the immunogenicity of ADX11-001 vaccination in patients with HPV+ 
squamous cell carcinoma of the oropharynx.  
1.1.2 To evaluate the tolerability, safety, and nature and degree of toxicity of ADX11-001 
by the numbers of patients with dose limiting toxicities (DLTs) and adverse events 
as assessed by the CTCAE v4.0  
1.2 Primary Endpoints 
1.2.1 The primary endpoint will be the change in HPV E6/E7-specific CD8+ cytotoxic 
lymphocyte (CTL) responses in the peripheral blood at time of surgery, with 
respect to baseline in vaccinated patients. 
1.2.2 Toxicity (NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0) 
1.3  Secondary Aim 
The secondary objective will be to determine vaccine-induced HPV E6/E7-specific CD8+ 
CTL responses in the blood at various timepoints after surgery, with respect to baseline 
levels, in vaccinated patients. 
1.4 Secondary Endpoint  
The secondary endpoint will be the change in HPV E6/E7-specific CD8+ cytotoxic 
lymphocyte (CTL) responses in the peripheral blood at various times after surgery (3W, 
6W, 3M, 6M, 12M), with respect to baseline in vaccinated patients. 
1.5 Exploratory Aim 
To analyze changes in the profile of tumor-infiltrating effector (NK cells, CD4+ and CD8+ 
T cells) and suppressor (Treg and MDSC) immunocytes by immunohistochemistry in 
vaccinated and unvaccinated (observational cohort) patients. 
 
 

 
 
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2 BACKGROUND/RATIONALE 
2.1 DISEASE AND INCIDENCE 
Squamous cell carcinoma is the most frequently occurring malignant tumor of the head and 
neck and is a major cause of morbidity and mortality worldwide. More than 90% of head and 
neck squamous cell carcinoma (HNSCC) originate from the mucosal linings of the oral cavity, 
pharynx, or larynx. Reports show that the estimated worldwide incidence of HNSCC in 2000 
was more than 551,000 with greater than 217,000 deaths.1 In the United States (US), in 2006 
alone, more than 46,000 new cases of HNSCC and 11,000 deaths due to HNSCC were 
reported.2 While HNSCC related to environmental carcinogens (tobacco, alcohol) has 
declined in the US, the incidence of certain subtypes of HNSCC, particularly HNSCC related 
to the human papilloma virus (HPV) is rising.3 
 
2.2 HPV-MEDIATED HEAD AND NECK CANCER – A TARGET FOR THERAPEUTIC 
VACCINATION 
Currently 60-80% of oropharyngeal cancer (OPC) is caused by the human papillomavirus 
(HPV), particularly the so-called “high-risk” oncogenic HPV16 and HPV18 genotypes. HPV 16 
is strongly implicated in the etiology of OPC4, and is found in up to 90% of virally-related OPC.5 
It has become increasingly clear that HPV-mediated OPC is a different disease from classical 
environmentally-related HNSCC, with distinct epidemiology and natural history. While patients 
with HPV+ tumors typically have an excellent response to surgical or radiation-based 
therapy6,7, treatment can be associated with significant short- and long-term toxicity, and it is 
not yet known whether patients with HPV+ OPSCCA have better long-term control. Thus, 
approaches which target the unique biology of HPV-infected cancer cells, such as therapeutic 
vaccination, are attractive strategies for potentially de-escalating XRT and chemo/XRT 
regimens (and thus decreasing toxicity) and enhancing long-term disease control.  
Prior to being internalized into epithelial cells in the basal layer of the oropharyngeal mucosa, 
HPV is susceptible to neutralization with specific antibodies, which is the mechanism of action 
of the preventative vaccine Gardasil.8 However, once HPV is internalized, it can integrate into 
the epithelial cell genome, and is no longer susceptible to antibody-mediated clearance. HPV-
infected cells can then only be cleared by mechanisms of cell-mediated immunity, including 
natural killer (NK) cells, and CD8+ cytotoxic T cells (CTL)9. In patients for whom these 
mechanisms are inefficient, progression of HPV-infected epithelial cells to malignancy is then 
driven by the E6 and E7 viral early genes, which inactivate p53 and Rb tumor suppressor 
genes respectively10. E6 and E7 are essential to maintenance of the transformed phenotype, 
and are also often recognized by T cells from HPV-infected patients11-13; thus these proteins 
are logical targets for monitoring HPV-specific immune responses, as well as therapeutic (cell-
mediated, or T cell-based) vaccination.  
Paradoxically, while patients with HPV-mediated tumors are unable to control and clear the 
virus, anti-HPV T cell responses can be detected9,11-13. Furthermore, a substantial amount of 
the HPV genome is devoted to various mechanisms of immune evasion14, and HPV-induced 
cancers are more common in immunosuppressed patients15,16. This suggests that the immune 
system does, in fact, recognize viral antigens in HPV-infected cells and the efficacy of this 
response depends critically on the overall balance of immune activation and 
immunosuppressive/immunoregulatory mechanisms in the host.  

 
 
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In an effort to tip the immunologic balance towards beneficial immune activation, preventive 
and therapeutic vaccines targeting HPV have been developed. Therapeutic peptide 
vaccination using long peptides specific for HPV16 has recently demonstrated to have 
immunologic and clinical efficacy in the treatment of vulvar intraepithelial neoplasia (VIN)49. 
The etiologic similarities between cervical cancer/VIN and HPV+ OPSCC, where in both the 
most common HPV subtype is HPV16, provide a convincing rationale for therapeutic 
vaccination in HPV+ OPSCCA patients.  
 
2.3 ADXS11-001 SUMMARY OF SAFETY 
As of June 30, 2016, 722 doses of ADXS11-001 have been administered to 290 enrolled 
subjects at doses of 5 x 107, 3.3 x 108, 1 x 109, 3.3 x 109, and 1 x 1010 CFU.  In the Phase 1 
study, 100% of subjects (n=15) have experienced flu-like AEs or symptoms associated with 
cytokine release syndrome. The incorporation of NSAIDs and antiemetic medications pre and 
post infusions has effectively reduced the incidence of these symptoms from 100% to 37%.  
In addition, a course of antibiotics is given 3 days after each dose of ADXS11-001 as a 
precautionary measure to ensure clearance of the Lm.  From the clinical experience in 290 
subjects, a clear pattern of mild to moderate treatment-related AEs consistent with cytokine 
release symptoms (e.g., constitutional symptoms such as fever, chills, rigors, headache, 
nausea, vomiting, tachycardia, shortness of breath, hypotension, and rash) are commonly 
seen and typically appear 2-4 hours after infusion.  Symptoms either self-resolve or respond 
quickly to symptomatic treatment. 
A summary of AEs in ≥5% of subjects by MedDRA system organ class and preferred term is 
presented in Table 1.  There have been no Grade 3-4 related AEs observed in over 5% of the 
subject population (see Table 1). 
 
Table 1  Treatment-Related (Possibly Related, Probably Related, Related) Adverse 
Events Reported ≥5% with ADXS11-001 (Safety Population, N=290) 
System Organ Class (SOC), Preferred Term, [N (%)] [1] 
Grades 1-4 
(N=290) 
Grade 3-4 
(N=290) 
Blood And Lymphatic System Disorders 
 
 
 
Anaemia 
178 (61.4) 
3(1.0) 
Cardiac Disorders 
 
 
 
Sinus Tachycardia 
16(5.5) 
2 (0.7) 
 
Tachycardia 
32 (11.0) 
 
Gastrointestinal Disorders 
 
 
 
Abdominal Pain 
49 (16.5) 
- 
 
Constipation 
47 (16.2) 
- 
 
Diarrhoea 
30 (10.3) 
1 (0.3) 
              Dysphagia 
15 (5.2) 
- 
 
Nausea 
107 (36.9) 
- 

 
 
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System Organ Class (SOC), Preferred Term, [N (%)] [1] 
Grades 1-4 
(N=290) 
Grade 3-4 
(N=290) 
 
Vomiting 
88 (30.3) 
4 (1.4) 
General Disorders And Administration Site Conditions 
 
 
 
Chills 
184 (63.5) 
5 (1.7) 
 
Disease Progression 
23 (7.9) 
- 
 
Fatigue 
74 (25.5) 
1 (0.3) 
 
Oedema Peripheral 
24 (8.3) 
- 
 
Pain 
34 (11.7) 
- 
 
Pyrexia 
167 (57.6) 
3 (1.0) 
Immune System Disorder 
 
 
               Cytokine Release Syndrome 
24 (8.3) 
13 (4.5) 
Investigations 
 
 
 
Alanine Aminotransferase Increased 
18 (6.2) 
2 (0.7) 
 
Aspartate Aminotransferase Increased 
21 (7.2) 
1 (0.3) 
 
Blood Alkaline Phosphatase Increased 
24 (8.3) 
3 (1.0) 
 
Blood Creatinine Increased 
25 (8.6) 
- 
 
Gamma-Glutamyltransferase Increased 
25 (8.6) 
4 (1.4) 
 
Haemoglobin Decreased 
16 (5.5) 
- 
 
White Blood Cell Count Decreased 
29 (10.0) 
2 (0.7) 
Metabolism And Nutrition Disorders 
 
 
 
Decreased Appetite 
33 (11.4) 
- 
 
Hyperglycaemia 
19 (6.5) 
- 
 
Hypertriglyceridemia 
20 (6.9) 
- 
 
Hypoalbuminaemia 
43 (14.8) 
- 
 
Hypokalaemia 
18 (6.2) 
- 
 
Hyponatraemia 
31 (10.7) 
1 (0.3) 
Musculoskeletal And Connective Tissue Disorders 
 
 
 
Back Pain 
33 (11.4) 
1 (0.3) 
Nervous System Disorders 
 
 
 
Dizziness 
19 (6.5) 
- 
 
Headache 
69 (23.8) 
- 

 
 
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System Organ Class (SOC), Preferred Term, [N (%)] [1] 
Grades 1-4 
(N=290) 
Grade 3-4 
(N=290) 
Psychiatric Disorders 
 
 
 
Anxiety 
17 (5.9) 
- 
 
Depression 
17 (5.9) 
- 
Respiratory, Thoracic And Mediastinal Disorders 
 
 
 
Cough 
16 (5.5) 
- 
 
Dyspnoea 
24 (8.3) 
2 (0.7) 
Vascular Disorders 
 
 
               Hypertension 
17 (5.9) 
3 (1.0) 
 
Hypotension 
58 (20.0) 
18 (6.2) 
Note:  [1] Percentage is calculated using column header count as denominator for percentage calculation. 
 
 
 
3    ADXS11-001 
3.1 Vaccine Design:  
ADXS11-001 (ADXS-HPV) is a live attenuated Listeria monocytogenes -listeriolysin O (Lm-
LLO) immunotherapy developed for the treatment of HPV-associated cancers. ADXS11-001 
is bioengineered to secrete an antigen-adjuvant fusion protein (tLLO-HPV-E7) consisting of a 
truncated fragment of the listeriolysin O (truncated LLO, tLLO) fused to the full length E7 
peptide of HPV-16.  
 
3.2 Mechanism of Action: 
ADXS11-001 is rapidly taken up by antigen presenting cells (APC) within the subject.  This 
causes activation of the APC and results in a multi-factorial stimulation of innate immunity.  To 
the subject, this activation can manifest as flu-like symptoms or symptoms associated with 
cytokine release that occur during or in the hours immediately following administration.  Once 
inside the APC, ADXS11-001 can escape the phagolysosome into the cytoplasm where it 
secretes the HPV­E7­tLLO fusion protein.  This peptide, along with other Lm peptides, is very 
rapidly ubiquitinated and transported to the proteasome where the peptides are broken down 
and cross-presented through major histocompatibility complex (MHC) Class 1 and Class 2 
pathways.  This cross-presentation, in immunologic context of responding to a “perceived” 
acute infection, stimulates the development of adaptive immunity culminating in HPV-specific 
effector T-cells that can infiltrate into the tumor microenvironment (TME) and destroy tumor 
cells immunologically. 
Advaxis Lm-LLO immunotherapies have broad effects on the immune system and the ability 
to neutralize mechanisms of immune tolerance.  These Lm-LLO immunotherapies take 
advantage of the ability of Lm to present target antigens in the cytoplasm of APCs that 
generate a target-specific T-cell immunity.  High avidity T­cells are generated where possible, 

 
 
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but when they are not, Lm stimulates an up-regulation of T-cell responses to sub-dominant 
epitopes.  Advaxis Lm-LLO immunotherapies secrete tumor peptides fused to LLO from 
multiple copies of plasmids.  This increased LLO secretion triggers endocrine and exocrine 
signaling of the immune system that results in a relative reduction in the number and function 
of regulatory T-cells and myeloid-derived suppressor cells (MDSC) in the TME, which enables 
tumor cell killing, even when the T-cells are lower avidity.  Tumor antigen specific T-cell 
immunity generated in the context of Lm-LLO immunotherapies can be effective even when 
targeting self-antigens or viral targets that are partially cross-reactive. 
Studies have shown that ADXS11-001 has anti-tumor activity against multiple types of high-
risk HPV, including cross-reactive activity where there are minor differences in HPV E7 T-cell 
epitopes.  As an investigational drug product, ADXS11-001 has no direct effect on the tumor 
tissue, but is designed to stimulate the subject’s own immune system to generate an effective 
immune response targeting the tumor-associated antigen like HPV-E7. 
 
4.0 TRANSORAL SURGERY – A UNIQUE OPPORTUNITY TO PROFILE THE TUMOR 
IMMUNE MICROENVIRONMENT (TIME) 
Increasing evidence suggests that the tumor immune microenvironment (TIME) of head and 
neck cancer is immunosuppressive, and that tumor-mediated immunosuppression may play 
a unique role in HPV-associated head and neck cancer. The TIME includes both anti-tumor 
effector cells (CD8+ cytotoxic T lymphocytes, CD4+ helper T cells, natural killer [NK] cells) 
and regulatory/suppressive immunocytes such as regulatory T cells (Treg) and myeloid-
derived suppressor cells (MDSC). Other factors, such as local concentrations of cytokines 
and chemokines also play a role in determining the TIME. The balance of effector and 
regulatory cells determines whether an individual TIME is associated with productive anti-
tumor immunity or localized immunosuppression and unrestrained tumor growth. While the 
majority of tumor vaccine studies examine circulating antigen-specific T cell responses, these 
responses do not always correlate with infiltration of antigen-specific T cells into the tumor 
and objective tumor responses. 
Transoral resection of oropharyngeal tumors can in some cases be accomplished under direct 
vision with conventional instruments, but generally involves either robot- or laser-assisted 
resection. Both transoral robotic surgery (TORS) and transoral laser microsurgery (TOLM) are 
intended to minimize or avoid morbidity of radiation therapy or chemo-radiation by completely 
removing the tumor in three dimensions with negative histological margins, thus allowing de-
escalation of adjuvant therapy in some patients and sparing adjuvant therapy altogether in 
others. When clinically indicated, a neck dissection is performed simultaneously. Both TORS 
and TOLM are FDA approved for head and neck cancer, and considered standard of care 
therapy of OPSCC in appropriate patients.  
An important distinction between transoral surgery and definitive chemoradiation as treatment 
for oropharyngeal tumors is that only surgery yields a pathological specimen which can be 
used to provide postoperative risk-stratification and guide the use of adjuvant therapy. The 
pathological specimen also permits evaluation of the response of tumor biomarkers and the 
TIME following a course of preoperative (also described as “neoadjuvant”) treatment. 
Transoral resection of oropharyngeal cancer provides a unique opportunity to evaluate the 
ability of vaccination to induce an immune response in the tumor and draining lymph nodes.  
 

 
 
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5.0 ELIGIBILITY AND SELECTION OF STUDY POPULATION 
5.1 INCLUSION CRITERIA 
To be enrolled in the study, the patients must meet the following inclusion criteria: 
1. The patient has newly-diagnosed, biopsy proven squamous cell carcinoma of Stage I-
IV (T1-3, N0-2b) of the oropharynx. 
2. The patient’s tumor is HPV positive by PCR or ISH assay of tumor biopsy. 
3. The patient is able/eligible to undergo treatment with transoral surgery (including 
TOLM or TORS) with or without neck dissection and with or without adjuvant radiation 
therapy or chemoradiation. 
4. The patient is able to understand and give informed consent. 
5. The patient is at least 18 years old. 
6. The patient’s ECOG performance status is </= 2. 
 
5.2 EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from the study: 
1. The patient has had prior head and neck squamous cell carcinoma (HNSCC), with the 
exception of superficial cutaneous basal cell or squamous cell carcinomas. 
2. The patient has active cancer in another part of the body, with the exception of 
superficial cutaneous basal cell or squamous cell carcinomas. 
3. If a cancer survivor, the disease free interval is less than 3 years, with the exception 
of superficial cutaneous basal cell or squamous cell carcinomas. 
4. If a cancer survivor, the patient received prior systemic chemotherapy or radiotherapy. 
5. If prior standard-of-care pre-treatment biopsy is inadequate for analysis by 
immunohistochemistry, and the patient is unwilling to undergo an additional biopsy 
procedure. 
6. The patient is a prisoner. 
7. The patient has a psychiatric illness or developmental delay that would interfere with 
understanding of the study and provision of informed consent. 
8. The patient has previously received definitive surgical, radiation, or chemoradiation 
treatment for HNSCC. 
9. The patient has a history of HIV or other known cause of immunosuppression, or is 
actively taking immunosuppressive medications due to organ transplantation, 
rheumatoid disease, or other medical conditions.  
10. The patient is allergic to naproxen or ibuprofen. 
11. The patient has a history of liver disease (excluding Gilbert’s disease and non-active 
Hepatitis C) and/or elevation of transaminases or bilirubin above the normal limit.  
12.  The 
patient 
has 
a 
contraindication 
(e.g. 
sensitivity/allergy) 
to 
both 
trimethoprim/sulfamethoxazole and ampicillin. 

 
 
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13. The patient has implanted medical device(s) that pose a high risk for colonization 
and/or cannot be easily removed (e.g., prosthetic joints, artificial heart valves, 
pacemakers, orthopedic screw(s), metal plate(s), bone graft(s), or other exogenous 
implant(s)).  NOTE: More common devices and prosthetics which include arterial and 
venous stents, dental and breast implants and venous access devices (e.g. Port-a-
Cath or Mediport) are permitted.  The study chair must be contacted prior to consenting 
any subject who has any other device and/or implant.  
14. Patients who are receiving or may receive future treatment with PI3K or TNFα 
inhibitors. 
15. Patients who have undergone a major surgery, including surgery for a new artificial 
implant and/or device, within 6 weeks prior to the initiation of ADXS11-001 treatment.  
NOTE: All toxicities and/or complications must have recovered to baseline or Grade 1 
prior to the initiation of ADXS11-001 study therapy.  Sponsor must be consulted prior 
to enrolling subjects on the study who recently had a major surgery or have new 
artificial implant, and/or devices. 
16. Patients who have a history of listeriosis or prior ADXS11-001 therapy. 
17. Patients with a known allergy to any component of the study treatment formulations. 
18. Pregnancy. The effects of this vaccine on the developing human fetus are unknown.  
For this reason women of child-bearing potential and men must use two forms of 
contraception (i.e., barrier contraception and one other method of contraception) at 
least 4 weeks prior to study entry, for the duration of study participation. Should a 
woman become pregnant or suspect she is pregnant while participating in this study, 
she should inform her treating physician immediately. 
Pregnancy Testing.  Women of childbearing potential are required to have a negative 
serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days prior 
to the first vaccine, within 24 hours prior to the first and second doses of vaccine and 
prior to surgery.  
Women of childbearing potential are defined as follows: 
• Patients with regular menses 
• Patients with amenorrhea, irregular cycles, or using a contraceptive method that 
precludes withdrawal bleeding 
• Women who have had a tubal ligation 
Women are considered not to be of childbearing potential for the following reasons: 
• The patient has undergone hysterectomy and/or bilateral oophorectomy. 
• The patient is post-menopausal defined by amenorrhea for at least 1 year in a 
woman > 45 years old. 
 
6.0 RESEARCH PLAN AND METHODS 
This is a window of opportunity single-arm phase II clinical trial in which a group of surgically-
resectable HPVOPC patients will receive the ADXS11-001 vaccine before standard-of-care 
transoral surgical resection. Vaccinated patients will be enrolled according to a Simon’s two-
stage design, with an initial cohort of 9 patients enrolled before preliminary analysis, and a 

 
 
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subsequent cohort of 13 patients enrolled if statistical criteria are met. To better understand 
the immunology of un-vaccinated HPVOPC patients, we will also enroll an optional 
observational group of up to 10 patients with the same characteristics who will undergo 
transoral resection without vaccination. We will collect, process and store tumor specimens, 
tumor-derived leukocytes, and serum and cellular components of peripheral blood, at different 
time points from study patients prior to analysis of batched samples at a later date once the 
specimens from 5 or more patients are available.   
 
 

 
 
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6.1 SCHEME:  
Figure 2.  Flow diagram for clinical trial of ADXS11-001 therapeutic HPV vaccine in HPV+ OPC patients. OPSCC – 
oropharyngeal squamous cell carcinoma. XRT – radiation therapy.  
 
 

 
 
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7.0 STUDY CALENDAR 
 
 
 
 
 
7.1Treatment Group 
 
Screening 
Treatment Week 
Pre-Op *5 
Surgery 
*6 
 
 
 
Post-Op 
 
Day -14 
to 0 
Day 
1 
Day 2 
Day 
4*9 
Day 
15 
Day 
16 
Day 
19*9 
Day 25 - 
35 
Day 28 - 
38 
Week 
3    +/-
1 week 
Week 
6  +/-1 
week 
3 
months  
+/-3 
weeks 
5 
months 
+/-2 
weeks 
6 
months  
+/-3 
weeks 
8 
months 
+/- 1 
month 
9 
months 
+/- 1 
month 
10 
months 
+/- 1 
month 
12 
month
s  +/- 1 
month 
Year 2 
and Year 
3 
+/- 1 
month 
1 
Informed Consent 
1 
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
 
  
 
2 
Inclusion/Exclusion 
Criteria 
1 
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
 
  
 
3 
Complete Medical 
History 
1 
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
 
  
 
4 
 Concomitant 
Medications** 
1 
2 
3 
4 
5 
6 
  
 7 
8  
9  
10 
11  
12 
 
13 
14  
 
5 
Assessment of 
Symptoms 
1 
2 
3 *8 
4 
5 
6 *8 
7 
8 
  
 9 
10  
11  
12 
13  
14 
 
15 
16 
 
6 
ECOG Performance 
Status 
1 
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
 
  
 
7 
Physical Examination 
1 
2 
3 
4 
  
5 
6 
  
 7 
8  
9  
10 
11 
12 
 
13 
14 
 
8 
Tumor Assessment  *1 
1 
2 
3 
4 
  
5 
6 
  
  
  
  
 
  
 
 
 
  
 
9 
CBC with differential 
1 
  
  
2  
  
3  
  
  
  
  
 
  
 
 
 
  
 
10 
CMP 
1 
  
  
2 
3 
  
  
  
  
 
  
 
 
 
  
 
11 
PT - PTT 
1 
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
 
  
 
12 
Research Blood 
1 
2 
  
3 
  
  
4 
  
5 
6 
7 
 
8 
 
 
 
9 
 
13 
Pregnancy Test 
1*14 
2 
 
 
3 
 
 
 4*13 
 
 
 
 
 
 
 
 
 
 
 
14 
CT Scan or MRI of the 
Head & Neck With and 
Without Contrast *2 
1 
  
  
  
  
  
  
2 
  
  
  
  
 
  
 
 
 
  
 
15 
Tumor Measurements 
*3 
1 
  
  
  
  
  
  
2 
  
  
  
  
 
  
 
 
 
  
 
16 
PET CT Scan *2 
1 
  
  
  
  
  
  
2 *7 
  
  
  
  
 
  
 
 
 
  
 
17 
Pathology for Tissue 
Analysis *4 
1 
  
  
  
  
  
  
  
2 
  
  
  
 
  
 
 
 
  
 
18 
HPV Testing (PCR) and 
p16 *4 
1 
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
 
  
 
19 
Vaccine 
Administration 
  
1 
  
  
2 
  
  
  
  
  
  
  
 
  
 
 
 
  
 

 
 
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Screening 
Treatment Week 
Pre-Op *5 
Surgery 
*6 
Post-Op 
 
 
Day -14 
to 0 
Day 
1 
Day 2 
Day 
4*9 
Day 
15 
Day 
16 
Day 
19*9 
Day 25 – 
35 
Day 28 – 
38 
Week 
3    +/-
1 week 
Week 
6  +/-1 
week 
3 
months  
+/-3 
weeks 
5 
months 
+/-2 
weeks 
6 
months  
+/-3 
weeks 
8 
months 
+/- 1 
month 
9 
months 
+/- 1 
month 
10 
months 
+/- 1 
month 
12 
month
s  +/- 1 
month 
Year 2 
and Year 
3 
+/- 1 
month 
20 
Vital Signs 
 
1 
*11 
 
 
2*11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
21 
Lm Surveillance 
Monitoring*10 
 
 
 
 
 
 
 
 
 
 
 
1 
 
2 
 
 
3 
 
4 
Every 4 
months 
(5-10) 
22 
Dispense/ Prescribe 
Oral Prophylactic 
Antibiotics 
 
1 
*12 
 
 
2*12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*1   Evaluate tumor or inflammation, size change or other indication of immune flare 
 
 
*2   Within 45 Days of registration 
*3   By RECIST 1.1 
 
 
 
 
 
 
 
 
*4   Local site’s Pathology Laboratory 
*5   Maximum 72 hrs before surgery 
 
 
 
 
 
 
*6   Pathology Report and Surgery Note will be collected as available 
*7   Optional to patient (Desired but not required) 
 
 
 
 
 
*8   by telephone call 
*9   Day 4 and 19 visits may be replaced by a phone call if patient is asymptomatic 
 
 
*10 Monitoring includes patient interview/exam and blood draws for labs and Listeria 
*11 Monitor vital signs every 30 minutes (± 5 minutes) immediately prior to and for the first 6  hours following the completion of every ADXS11-001 infusion 
*12 7-day course of oral antibiotic therapy starting approximately 72 hours after administration of ADXS11-001, if Patient discontinues the study anytime  - 6 month course of oral trimethoprim/sulfamethoxazole or 
ampicillin 
*13 Standard of care test 
*14 To be done within 10 -14 days prior to vaccine 1 

 
 
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7.2 Observational Group 
 
 
Screening 
Pre-Op 
*5 
Surgery 
*6 
Post-Op  
Week 3    
+/-1 
week 
Week 6  
+/-1 
week 
3 months  
+/-3 
weeks 
6 months  
+/-3 
weeks 
12 Months  
+/- 1 month 
1 
Informed Consent 
1 
  
  
  
  
  
  
  
2 
Inclusion/Exclusion Criteria 
1 
  
  
  
  
  
  
  
3 
Complete Medical History 
1 
  
  
  
  
  
  
  
4 
List of Medications 
1 
2 
  
 3 
4  
5  
6  
7  
5 
Assessment of Symptoms 
1 
2 
  
 3 
4  
5  
6  
7  
6 
ECOG Performance Status 
1 
  
  
  
  
  
  
  
7 
Physical Examination 
1 
2 
  
 3 
4  
5  
6  
7  
8 
Tumor Assessment  *1 
1 
2 
  
  
  
  
  
  
9 
CBC with differential 
1 
  
  
  
  
  
  
  
10 
CMP 
1 
  
  
  
  
  
  
  
11 
PT - PTT 
1 
  
  
  
  
  
  
  
12 
Research Blood 
1 
4*7 
  
5 
6 
7 
8 
9 
13 
CT Scan or MRI of the Head & 
Neck With and Without 
Contrast *2 
1 
  
  
  
  
  
  
  
14 
Tumor Measurements *3 
1 
  
  
  
  
  
  
  
15 
PET CT Scan *2 
1 
  
  
  
  
  
  
  
16 
Pathology for Tissue Analysis 
*4 
1 
  
2 
  
  
  
  
  
17 
HPV Testing (PCR) and p16 *4 
1 
  
  
  
  
  
  
  
18 
Vaccine Administration 
  
  
  
  
  
  
  
  
*1 
Evaluate tumor or inflammation, size change or other indication of immune flare 
*2 
Within 45 days of vaccination  
*3 
By RECIST 1.1 
*4 
 Local Site’s Pathology Laboratory 
*5 
Maximum 72hrs before surgery 
*6 
Pathology Report and Surgery Note will be collected as available  
*7 
Patient in this group will not undergo research blood Draw #2 and #3. 
 
 
 
 

 
 
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8.0 PATIENT IDENTIFICATION, CONSENT, SCREENING, HPV TESTING, ASSIGNMENT 
 
8.1 Patients with biopsy proven squamous cell carcinoma of the oropharynx who are to 
undergo transoral surgical resection with or without neck dissection will be approached 
for participation in the study at the Head and Neck  Clinic at each site. 
 
8.2 Informed consent will be obtained by a co-investigator or authorized clinical research 
coordinator. 
 
8.3 After the patient signs the informed consent, the patient will be registered for screening 
on the each site’s EDC (Electronic Data Capture) system. If any question arises during 
screening process, please contact Study chair at 713-798-3909 and/or Yesenia 
Ramirez at 713-798-8541.  
 
8.4 Once the investigator has verified that the patient meets all inclusion/exclusion criteria, 
the patient will be registered for and started on therapy. The screening process will 
consist of the following: 
1. Signed informed consent form 
2. Eligibility (Inclusion/exclusion) checklist 
3. Complete medical history*  
4. List of concomitant medications, taken in the 28 days prior to first vaccine dose 
5. Assessment of baseline symptoms 
6. ECOG Performance Status  
7. Physical examination, including height, weight, and vital signs  
8. Tumor Assessment by direct examination 
9. Complete blood count with differential 
10. Complete metabolic panel 
11. Prothrombin time, partial thromboplastin time 
12. PET/CT and CT/MRI with or without contrast of the head and neck (within 45 days 
before registration) 
13. Tumor measurements by RECIST 1.1. 51 
14. Tissue analysis, HPV testing (PCR) and p16 tests by local lab – pathological material 
is required for both tests.   
 
*Surgical history must be included within the complete medical history. Documentation 
of non-cancer surgeries, including, but not limited to artificial (prosthetic) joints, 
implants and/or devices, such as port/stent implant placed prior to study enrollment. 
8.5 HPV Testing: HNSCC patients undergo routine pre-treatment biopsy of the primary 
tumor to ensure an accurate diagnosis and allow treatment planning. Following 
standard-of-care biopsy of the primary tumor, HPV testing will be confirmed prior to 
vaccination by HPV type-specific PCR for HPV subtype 16 and other oncogenic 
subtypes. HPV testing will be performed in the designated laboratory at each site. The 
results of PCR testing will be reported to the patients as a research, not a clinical 
procedure. 
 
 

 
 
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8.6 Following entrance into the study, appropriate patients will be assigned to the vaccine 
arm by the local site PI. This group will be compared with an observational group of 
similar patients that will be treated with transoral surgery without vaccination during 
the same period of time. Since the design of this study is to compare patients’ pre- and 
post-treatment assay results rather than results from vaccinated versus unvaccinated 
patients, assignment to treatment or observational group will not be randomized. 
Rather we will offer enrollment in the observational group to patients who do not wish 
to receive the vaccine but are willing to enroll in the observational portion of this trial.    
 
9.0  
ADXS11-001 Safety Precautions, Handling and Preparation Instructions 
9.1 Description:  ADXS11-001 is a free flowing isotonic, aqueous, cream colored suspension 
at a pH of 6.8-7.8 supplied in a DIN 2R glass vial (4mL), stoppered with a grey rubber 
stopper and sealed with an aluminum seal and a blue flip off cap that must be stored 
frozen at -80 ± 10°C. 
9.2 How Supplied:  ADXS11-001 is provided on dry ice via bonded courier delivery with 
temperature monitors in 1.2 mL vials of which 1.0 ml is to be used in the preparation of a 
dose.  ADXS11-001 must be received frozen on dry ice and immediately stored at -80 ± 
10°C.  ADXS11-001 is stable for 6 hours when stored at room temperature (temperatures 
at or below 25°C [77°F]). This 6 hour time allows for vial thaw, preparation of infusion and 
administration.  The 60 minute ADXS11-001 infusion at room temperature must be 
completed within 6 hours of product vial removal from freezer. 
9.3 Storage and Stability:  ADXS11-001 must be received frozen on dry ice and immediately 
stored at -80 ± 10°C. 
• 
Even though ADXS11-001 is non-pathogenic, all L. monocytogenes species are 
classified as Biosafety Level 2 (BSL-2) according to the Biosafety in 
Microbiological and Biomedical Laboratories (BMBL) 5th Edition.  Universal 
precautions and institutional guidelines should be used when handling 
investigational drugs and human specimens. 
• 
Aseptic technique must be strictly observed throughout the preparation procedure 
including the use of a biologic safety cabinet or hood since ADXS11-001 is live, 
attenuated L. monocytogenes. 
• 
Prior to preparation, the frozen vial of ADXS11-001 should be thawed at room 
temperature at or below 25°C (77°F) for approximately 5 to 10 minutes. 
• 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration. Discard the drug product vial if extraneous 
particulate matter other than slightly turbid white to off white suspension is 
observed. 
• 
Do not use ADXS11-001 if discoloration is observed. 
• 
Each dose of ADXS11-001 must be prepared in sterile 0.9% Sodium Chloride 
Injection, USP (normal saline) and patient must be dosed within 6 hours of drug 
product removal from the freezer. 
• 
ADXS11-001 MUST NOT BE MIXED WITH OTHER DILUENTS. 
• 
Once the vial is removed from the freezer, the ADXS11-001 product is stable at 
room temperature (temperatures at or below 25°C [77°F]) for 6 hours.  The 6 hours 

 
 
 V11.2 (1/9/20) 
 
 
 
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includes the drug product vial thaw, dose preparation, room temperature storage 
of the prepared dose in the IV bag AND the duration of infusion. 
• 
DO NOT ADMINISTER THE PRODUCT AS AN (INTRAVENOUS [IV] PUSH OR 
BOLUS). 
• 
DO NOT COMBINE, DILUTE OR ADMINISTER IT AS AN INFUSION WITH 
OTHER MEDICINAL PRODUCTS. 
• 
ADXS11-001 must be administered through a separate and distinct infusion line.  
ADXS11-001 must not be administered via an existing or newly placed central 
venous catheter or infusion port which 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 ADXS11-001 infusion and following the 
subject’s first post-treatment dose of oral antibiotics. 
9.4 Safety Precautions:  ADXS11-001 is classified a BSL-2, minimally pathogenic.  
Precautions as stated in the BMBL 5th Edition59  include: 
 
Agent: ADXS11-001, live attenuated genetically engineered live vaccine  
ADXS11-001 is a live attenuated strain of Listeria monocytogenes (Lm) that has 
been attenuated such that it is cleared by severe combined immunodeficiency (SCID) 
mice lacking cellular immunity and gamma interferon knock-out mice lacking adaptive 
immunity.  It has also been altered such that it is impossible for it to recombine with wild-
type Lm.  In the Phase 1 study no bacterial shedding was detected from any subjects 
treated with ADXS11-001.  It is considered as a non-infectious BSL-1 agent for transport 
by the CDC. 
 
Wild type Listeria is Gram-positive, non-spore-forming, facultative bacilli that are 
hemolytic and catalase-positive.  It is a naturally occurring bacterium that is present in 
the environment and is known to cause illness in some people when they eat foods 
contaminated with Lm.  Although healthy adults and children can contract a wild-type 
Listeria infection, they do not usually become seriously ill.  People at risk of severe illness 
from wild-type Listeria are pregnant women, newborns, and persons with impaired 
immune function. 
 
Even though ADXS11-001 is non-pathogenic, all Lm species are classified as BSL-2 
according to the BMBL 5th Edition.  Universal precautions and institutional guidelines 
should be used when handling investigational drugs and human specimens.  Except for 
the transmission of mother to fetus, human-to-human transmission of Lm is not known to 
occur60 .  Shedding studies completed in Phase 1 demonstrated that, in the absence of 
antibiotics, ADXS11-001 was rapidly cleared from the blood with no Lm detected in the 
blood of any subject beyond 48 hours post-dosing, and no Lm was detected in the urine 
and feces in any subject at the highest dose of ADXS11-001 tested (1 x 1010 CFU)52 . 
 
Based on the mechanism of action of ADXS11-001 and the inability of Lm to be 
transferred from human-to-human, there is no need for subjects who receive ADXS11-
001 to avoid contact with people who are elderly, pregnant, newborns, or have weakened 
immune systems. 
 

 
 
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Page 19 of 50 
 
Precautions as stated in the BMBL 5th Edition include: 
 
Wild-type L. monocytogenes poses a potential hazard to laboratory personnel.  The 
Gram-positive, non-spore-forming, aerobic bacilli are hemolytic and catalase-
positive. Bacteria have been isolated from soil, dust, human food, animals, and 
asymptomatic humans. Most cases of listeriosis have arisen from eating 
contaminated food products, most notably soft cheeses, raw meat, and unwashed 
raw vegetables.  Although healthy adults and children can contract a Listeria 
infection, they do not usually become seriously ill. At risk of severe illness are 
pregnant women, newborns, and persons with impaired immune function. 
 
Laboratory Hazards: Wild-type Listeria monocytogenes are ubiquitous in the 
environment and may be found in feces, cerebrospinal fluid (CSF), and blood, as well as 
food and environmental materials. Ingestion is the most common mode of exposure, but 
wild-type Listeria can also cause eye and skin infections following a direct exposure. Wild-
type Lm infections in pregnant women occur most often in the third trimester and may 
precipitate labor. Transplacental transmission of Lm poses a grave risk to the fetus and 
may result in disseminated abscesses contributing to a mortality rate of nearly 100%. 
 
Recommended Precautions: BSL-2 practices, containment equipment, and facilities 
are recommended for activities with clinical specimens and cultures known or suspected 
to contain the agent. Gloves and eye protection should be worn while handling the agent.  
Pregnant women who work with Lm in the clinical or research laboratory setting should 
be fully informed of the potential hazards associated with the organism, including 
potential risks to the fetus. 
 
Disposing of Contaminated Materials:  Gloves should be used while cleaning spills.  
Unless ingested orally or parenterally no pathologic hazard exists.  Contaminated 
materials can be disposed of in sealed containers as medical waste (e.g. closed plastic 
bags).  Spills should be washed and cleaned with the application of commercial chlorine 
bleach (e.g. Clorox). 
9.5 Drug Preparation and Administration:  Only sterile containers will be used in the 
preparation of these materials.  They may be autoclaved glassware, disposable 
containers, or other sterile materials as provided for within each institution’s SOP. 
 
 
Please note that ADXS11-001, the Investigational Study Drug, is a live, 
highly attenuated microbe, L monocytogenes, which can multiply, thus 
increasing the dosage, or die off, thus decreasing the dosage.  
ADXS11-001 is stable for 6 hours when stored at room temperature 
(temperatures at or below 25°C [77°F]). This 6 hour time allows for vial 
thaw, preparation of infusion and administration.  The 60 minute 
ADXS11-001 infusion at room temperature must be completed 
within 6 hours from product vial removal from the freezer.   
 
 

 
 
 V11.2 (1/9/20) 
 
 
 
Page 20 of 50 
 
A dose of study drug is prepared in the following manner: 
 
Remove the appropriate number of vials from -80 ± 10°C and thaw the vials at room 
temperature for approximately 5 to 10 minutes.  Gently agitate mildly by hand to ensure 
that the study drug is in suspension.  Prepare the dose and infusion volume of ADXS11-
001 as described below. 
 
To make a dose of 1 x 109 cfu (Drug Product concentration of 1.9x109 cfu/mL):  Thaw 
1 vial of the ADXS11-001 study drug at room temperature (temperatures at or below 25°C 
[77°F]). Gently agitate the vial mildly by hand to ensure that the study drug is in 
suspension. Withdraw 0.53 mL of ADXS11-001 suspension and add it to the infusion bag 
for a final volume of 500 mL and mix thoroughly. 
 
Each prepared dose of ADXS11-001 must be administered at room temperature 
(temperatures at or below 25°C [77°F]) within 6 hours from product vial removal 
from the freezer.  This includes vial thaw, room temperature storage of the vial, 
dose preparation, storage of the infusion suspension in the IV bag and the duration 
of the infusion.  Administer ADXS11-001 at room temperature intravenously over a 
60-minute infusion time. 
 
The time the vial is removed from the freezer is to be recorded (T0). 
 
Doses will be administered to patients who have received the prophylactic medication 
specified in the protocol as a 60 minute intravenous (IV) infusion. The actual time of 
administration is to be recorded (T1). The actual time the infusion is completed is to be 
recorded (T2). 
 
9.6 Drug Ordering and Distribution:  Please see Appendix A.   
 
10.0 VACCINATION OF PATIENTS WITH ADXS11-001 
Two vaccinations with ADXS11-001 will be given at a dose of 1x109 cfu intravenously 
according to the schedule described in the Study Calendar above.  The drug will be given 
by a 500ml infusion over 60 minutes through a separate and distinct infusion line with each 
infusion and this line is to be used for prophylactic medication, pre-medication and ADXS11-
001 administration. The line is to be removed prior to patient leaving the clinic and a new line 
is to be placed with each administration. For safety monitoring purposes, enrollment of the 
first 3 subjects at any site will be staggered by at least 2 weeks. Once any site has enrolled 
3 subjects, then all sites can enroll subjects concurrently.  
ADXS11-001 must not be administered via an existing or newly placed central venous 
catheter or infusion port which is planned to be used for another purpose.  In addition, the 
central venous catheter or infusion port must not be used for a minimum of 72 hours following 
the completion of the ADXS11-001 infusion AND following the subject’s first dose of oral 
antibiotics. 
10.1    Pre-treatment prophylactic medication regimen:  Mild to moderate cytokine release 
symptoms (e.g., constitutional symptoms such as fever, chills, rigors, fatigue, headache, 
nausea, vomiting, tachycardia, shortness of breath, hypotension and rash) are commonly 

 
 
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seen and typically occur 2-4 hours after ADXS11-001 infusion and often resolve within 12-24 
hours. Prophylactic medications are intended to reduce the inflammatory response.  Subjects 
should receive the following pretreatment prophylaxis regimen. 
 
IV Fluid Hydration: 
• 
Normal saline (e.g., 500 mL over approximately 30-60 minutes) 
 
Premedication Regimen: 
• 
Antihistamine – PO or IV (e.g. diphenhydramine 25 mg or equivalent),  once 
• 
NSAIDs - PO (e.g., naproxen 220 mg or ibuprofen, 400 mg), once 
• 
Antiemetic - PO or IV (e.g., promethazine or ondansetron), once 
• 
Histamine H2-receptor antagonist – PO or IV (e.g., famotidine 20 mg or equivalent) 
Pretreatment medication should be given on the day of dosing and completed at least 30 
minutes prior to the start of the assigned study treatment.  Additional NSAID doses and 
antiemetic administration should be given per label or package insert post initial 
administration on Day 1 and Day 2 of the ADXS11-001 infusion, as needed.  The 
prescribed dosage of the selected NSAID and antiemetic will be at the discretion of the 
Investigator.   
Do not substitute acetaminophen for the selected NSAID for prophylactic treatment since 
acetaminophen does not have similar anti-inflammatory properties that could ameliorate 
cytokine release symptoms.   
 
10.2 
After each vaccination, subjects will receive a 7-day course of oral antibiotic therapy 
starting approximately 72 hours after administration of ADXS11-001.  Antibiotic therapy 
should consist of either 160 mg trimethoprim/800 mg sulfamethoxazole (DS) tablet 
administered three times a week for 7 days or 80 mg trimethoprim/400 sulfamethoxazole 
administered daily for 7 days. In subjects with a sulfa allergy, prophylactic antibiotic therapy 
should consist of ampicillin 500 mg four times daily for 7 consecutive days starting 
approximately 72 hours after administration of ADXS11-001. 
 
10.3 
Treatment is to be done on an outpatient basis.  Patients will be observed in the outpatient 
area for 6 hours following the ADXS11-001 infusion.  Vital signs will be taken pre-dose, and 
every 30 min for 6 hours after each dose. 
 
10.4 
Criteria for discharge from observation:  At 6 hours after the dose, the patient must have 
a temperature less than 38.5 degrees C and other vital signs (heart rate, blood pressure, and 
respiration) must be within normal limits.  The patient must not show signs or symptoms of 
moderate-severe nausea, vomiting, or headache.  If the patient does not meet these 
discharge criteria, the patient should be admitted to the hospital for observation and treatment 
of side effects.  
 
For those patients stable for discharge the study team will contact the patient by telephone 
at one and three days following administration of the vaccine to determine if any adverse 
events have occurred.  

 
 
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10.5 
Safety follow-up will be conducted via a telephone call 30 days (±5 days) after the last 
ADXS11-001 infusion or in week 1 visit post surgery to confirm the resolution of any 
ongoing AEs and SAEs. Subjects will also continue to be monitored for adverse and serious 
adverse events during the 3 year Lm surveillance monitoring period of the study.  
 
10.6 
Subjects will receive a 6 month course of oral trimethoprim/sulfamethoxazole or ampicillin 
for subjects with sulfa allergies to be initiated approximately 72 hours of resuming oral intake 
after transoral surgery, or at the time of study discontinuation. For those patients for whom 
resumption of oral intake is delayed beyond 72 hours, an alternative delivery route (e.g. 
gastrostomy tube) may be employed. Trimethoprim/sulfamethoxazole therapy should consist 
of either 160 mg trimethoprim/800 mg sulfamethoxazole (DS) tablet administered three times 
a week or 80 mg trimethoprim/400 mg sulfamethoxazole administered daily for 6 months.  
The dose of ampicillin consists of 500 mg four times daily for 6 months.  Review the approved 
product labeling for Bactrim and ampicillin, and monitor antibiotic tolerance as dosing 
adjustments may be necessary. 
 
 
10.7 
Lm Surveillance Monitoring:  In addition, all subjects will participate in a three-year Lm 
surveillance period. Surveillance monitoring for the detection of Lm will be initiated at the 
completion of study treatment according to the protocol or at the time of study discontinuation 
if earlier. This surveillance monitoring period will consist of a 6-month course of oral 
antibiotics, obtaining a blood sample to monitor CBC, CMP, including CRP and ESR, and 
blood cultures at regular intervals.  This testing will be performed on all subjects who have 
received at least 1 dose of ADXS11-001.  It will occur at  3 months (+/- 2 weeks), 6 months(+/- 
3 weeks), 9 months(+/- 1 Month), 12 months (+/- 1 Month),  and every 4 months(+/- 1 Month) 
for year 2 and year 3 postoperatively.  If a persistent increase in CRP and/or ESR is observed 
with negative blood cultures for Listeria during this time, the subject should be evaluated and 
treated, as appropriate, for another possible cause.  In the event that a definite cause has not 
been identified, subjects must continue to be monitored closely, including additional testing 
and a blood culture, for possible signs/symptoms of listeriosis.  This testing may be performed 
at the investigational site or at another acceptable location following consultation with the 
study chair. 
10.8 
Treatment modification: The dose of ADXS11-001 will not be modified (i.e., reduced or 
increased).  However, treatment may be delayed or discontinued based on toxicities, as 
shown below in Table A. 
Treatment modification and supportive care guidelines for cytokine release are included in 
Appendix A and for infusion related toxicities are included in Appendix B.   
 
 

 
 
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Table A: Treatment Delay/Discontinuation Guidelines for Drug-Related Adverse Events 
Toxicity 
Grade 
Result 
Action 
Hematologic 
and non-
hematologic, 
excluding 
cytokine 
release 
symptoms 
1-2 
 
Continue therapy 
3 
 
Toxicity resolves to ≤ Grade 1 
or baseline within 2 
weeks of last infusion 
Restart therapy 
3 
 
Toxicity not resolved to  
≤ Grade 1 or baseline 
within 2 weeks of last 
infusion 
Discussion with study chair 
required 
4 
 
Permanent discontinuation 
from Study 
In case toxicity does not resolve to Grade 0-1 within 2 weeks after the last infusion, trial 
treatment should be discontinued after consultation with the Sponsor.  With Investigator and 
Sponsor agreement, subjects with a laboratory AE still at Grade 2 after 2 weeks may continue 
treatment in the trial only if asymptomatic and controlled.  For information on the management 
of AEs, see Section 4.6 (Supportive Care). 
10.9 
MAJOR AND MINOR SURGERIES AND ADXS11-001 TREATMENT:  No formal studies 
of the effect of ADXS11-001 on wound healing have been conducted.  However, based on 
its mechanism of action it is not expected that administration of ADXS11-001 would 
complicate wound healing.  Therefore, a subject may initiate or resume study treatment 2 
weeks after minor surgery (i.e., surgery involving little risk to the life of the subject; specifically 
an operation on the superficial structures of the body or a manipulative procedure that does 
not involve a serious risk) if the wound has completely healed and there are no wound healing 
complications.  A subject who has wound healing complications following minor surgery, 
received major surgery or requires new implants and/or devices (permitted by the protocol) 
during the course of the study, must wait a minimum of 6 weeks and must have recovered 
from any toxicity (e.g., return to baseline or Grade 1) and/or complication before the next 
infusion of study treatment.  Sponsor consultation is required prior to resuming study 
treatment for these subjects.  If the treatment is delayed due to concomitant surgery beyond 
12 weeks, the subject may be discontinued from the study. 
 
10.10 ADVERSE EVENTS AND SUPPORTIVE CARE: The most likely AEs associated with 
ADXS11-001 are comprised primarily of individual flu-like symptoms (e.g., fever, chills, body 
ache, and fatigue) or cytokine release symptoms (e.g., headache, nausea, vomiting, tachycardia, 
shortness of breath, hypotension and rash).  The symptoms usually present within 2-4 hours after 
the completion of infusions and are often mild to moderate and transient in nature or responds 
quickly to symptomatic treatment.   In rare instances they may last up to 24 hours.  No cumulative 
toxicity has been observed. 
Less likely AE’s include increase heart rate, low blood pressure, muscle aches, headaches, 
allergic reaction, changes in blood chemistry, changes in blood counts, and short term changes 
in liver function. 
Rare but serious AEs include high fever, difficulty breathing and hypotension. 

 
 
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Like all Listeria, ADXS11-001 has a tropism for the liver.  Transient asymptomatic elevations of 
ALT and alkaline phosphatase were observed after dosing in the Phase 1 trial without 
prophylactic medication administration.  For that reason, patients with significant liver disease 
are excluded, and particular attention is to be paid to hepatic abnormalities. 
10.10.1 
Supportive Care Guidelines:  The major safety findings with ADXS11-001 occurring in 
>5% of subjects, as of June 2016 (n=290) and being possibly, probably or definitely related 
include anemia (61.4%), chills (63.5%), fatigue (25.5%), fever (57.6 %), nausea (36.9%), 
vomiting (30.3%), headaches (23.8%).  Most are Grade 1-2 in severity.  Subjects should 
receive appropriate supportive care measures as deemed necessary by the treating 
Investigator with consideration given to the criteria the items outlined below.   
Nausea and vomiting- should be treated aggressively, and consideration should be given in 
subsequent cycles to the administration of prophylactic antiemetic therapy according to standard 
institutional practice.  Subjects should be strongly encouraged to maintain liberal oral fluid intake.  
Cytokine Release Symptoms- are a constellation of inflammatory symptoms resulting from 
cytokine elevations associated with T cell engagement and proliferation.  Symptoms related to 
cytokine release may include constitutional symptoms such as fever, chills, rigors, fatigue, 
headache, nausea, vomiting, rash, tachycardia, hypotension and shortness of breath which 
usually presents several hours after the infusion and lasts for up to 24 hours.  These symptoms 
are caused by an increase in cytokines such as TNFα, IFNγ and IL-6, all of which have been 
shown to occur after ADXS11-001 administration, resulting from the body’s immune response to 
the therapy.  Although, symptoms are often Grade 1-2 and transient, resolving with symptomatic 
management within 30 minutes to 1 hour, in some instances (~6%) Grade 3-4 hypotension has 
been seen.  Therefore, close monitoring of blood pressure is strongly recommended at baseline, 
and during the post-infusion period.  Increased levels of IL-6 have been strongly associated with 
capillary leak which manifests as hypotension due to the cytokines involved.  We have observed 
elevated IL-6 levels after infusion of ADXS11-001, with peak levels occurring 2-4 hours after 
infusion.  Emerging evidence indicates that IL-6 antagonists, such as tocilizumab, have 
demonstrated good results in treating cytokine-induced hypotension [61, 62, 63, 64] and are 
therefore recommended for cases of severe hypotension refractory to supportive care (e.g., fluids 
and/or pressors).  
The management of cytokine release symptoms and guidelines for subsequent treatment for 
subjects who have experiences these AEs are shown in the table below. 
 
 

 
 
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Table B  Recommended Management Guidelines for Adverse Events Associated with Cytokine Release 
Toxicity 
NCI 
CTCAE 
Grade or 
Severity 
Treatment 
Modification for Subsequent 
infusions 
Hypotension 
1 
Mild 
• 
Supportive care 
• Increase pretreatment IV fluids 
(e.g., 500 ml -1L normal saline) 
All other cytokine release 
symptoms (e.g. chills, rigors, 
fever, nausea, vomiting) 
1 
• 
Supportive care 
• No modification 
Hypotension 
 
2 
Moderate 
• 
Fluids and 1 dose of pressor (e.g. 0.3 mg 
epinephrine IM)  
• 
Increase monitoring of vital signs 
• 
If hypotension persist for more than one 
hour consider low dose corticosteroids 
(e.g. hydrocortisone 100 mg IV over 30 
seconds 
• Extend infusion time to 2 hours.  
• Increase pretreatment IV fluids (e.g. 
500 ml -1L normal saline)  
• Incorporate Glucocorticoid- 
Hydrocortisone or equivalent- 50 
mg, IV, as premedication 
 
All other cytokine release 
symptoms (e.g. chills, rigors, 
fever, nausea, vomiting) 
2 
• 
Appropriate supportive care measure 
• Extend infusion time to 2 hours.  
• Consider increasing doses of 
prophylactic medications 
Hypotension 
3 
Severe 
• 
Fluids, high dose pressors (e.g. Dopamine 
10 µg/kg/min)  +1 dose 
tocilizumab*(4mg/kg over 1 hour) 
• 
If hypotension worsens or is unresponsive 
to above measures, administer 
corticosteroids 
• Discuss with Sponsor 

 
 
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Toxicity 
NCI 
CTCAE 
Grade or 
Severity 
Treatment 
Modification for Subsequent 
infusions 
• 
If the subject’s condition does not improve 
or stabilize within 24 hours of the 
tocilizumab dose, administration of a 
second dose of tocilizumab +/- 
corticosteroids should be considered. 
All other cytokine release 
symptoms (e.g. chills, rigors, 
fever, nausea, vomiting) 
3 
• 
Appropriate supportive care  measures 
• Extend infusion time to 2 hours.  
• Consider increasing doses of 
prophylactic dose of NSAID, or 
antiemetic as appropriate 
Hypotension/ 
Organ toxicity, mechanical 
ventilation 
4 
Life 
threatening 
• 
Vigilant supportive care 
• 
Fluids 
• 
High dose  pressors,  
• 
Tocilizumab (4mg/kg over 1 hour) +/- 
corticosteroids (hydrocortisone 100 mg IV 
infused over 30 seconds administered 
every 2 hours until symptoms resolve to 
<Grade 1) 
• Permanently discontinue 
* Tocilizumab is a humanized, immunoglobulin G1k (IgG1k) anti-human IL-6R mAb approved for treatment of adult subjects 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 subjects 2 years of age and older.  Tocilizumab works by preventing IL-6 binding to both cell-
associated and soluble IL-6Rs. Although, it is not indicated for the treatment of cytokine release symptoms emerging clinical experience at several institutions has 
concluded that tocilizumab is an effective treatment for severe or life-threatening cytokine release symptoms. [61, 62, 63, 64]

 
 
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Management of infusion reactions- While there is some overlap between the symptoms of 
cytokine release and infusion reactions, infusion reactions typically occur during the infusion, 
while symptoms associated with cytokine release typically occur after the infusion and are 
mediated by a different mechanism of action.  Signs/symptoms of infusion reactions may 
include: allergic reaction/ hypersensitivity (including drug fever); arthralgia (joint pain); 
bronchospasm; cough; dizziness; dyspnea (shortness of breath); fatigue (asthenia, lethargy, 
malaise); headache; hypertension; hypotension; myalgia (muscle pain); nausea; 
pruritis/itching; rash/ desquamation; rigors/chills; sweating (diaphoresis); tachycardia; tumor 
pain (onset or exacerbation of tumor pain due to treatment); urticaria (hives, welts, wheals); 
vomiting. 
Table C below shows the management guidelines for subjects who experience an infusion 
reaction associated with administration of ADXS11-001. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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

 
 
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10.10.2 
Listeriosis and Listeria Infection-Identification and Management 
A person with wild type (wt) listeriosis usually presents with fever and muscle aches, sometimes 
preceded by diarrhea or other gastrointestinal symptoms.  Almost everyone who is diagnosed 
with listeriosis has an "invasive" infection, in which the bacteria spread beyond the gastrointestinal 
tract.  The symptoms vary with the infected person.  Pregnant women typically experience fever 
and other non-specific symptoms, such as fatigue and aches.  However, infections during 
pregnancy can lead to miscarriage, stillbirth, premature delivery, or life-threatening infection of 
the newborn.  In people other than pregnant women, symptoms can include headache, stiff neck, 
confusion, loss of balance, and convulsions in addition to fever and muscle aches.  Listeriosis can 
present in different ways.  In older adults and people with immunocompromising conditions, 
septicemia and meningitis are the most common clinical presentations.[58]  Subjects may need 
immediate evaluation with a brain CT scan or MRI and a lumbar puncture with the analysis of 
spinal fluid to rule out meningitis. 
For symptomatic subjects, diagnosis is confirmed only after isolation of Lm from a normally sterile 
site, such as blood or spinal fluid (in the setting of nervous system involvement), or amniotic 
fluid/placenta (in the setting of pregnancy).  Stool samples are of limited use and are not 
recommended.  Lm can be isolated readily on routine media, but care must be taken to distinguish 
this organism from other Gram-positive rods, particularly diphtheroids.  Selective enrichment 
media improve rates of isolation from contaminated specimens.  You can expect that the cultures 
will take approximately 1-2 days for growth.  Importantly, a negative culture does not rule out 
infection in the presence of strong clinical suspicion.  Serological tests are unreliable, and not 
recommended at the present time [58]. 
Listeriosis is treated with a wide range of antibiotics.  In preclinical studies, wt-Lm and ADXS11-
001 are susceptible to the lowest tested concentration of the following antimicrobial agents:  
ampicillin, amoxicillin/K clavulanate, ciprofloxacin, erythromycin, gentamicin, penicillin, 
tetracycline, trimethoprim/sulfamethoxazole and vancomycin (IV).  ADXS11-001 is resistant to 
both streptomycin and chloramphenicol.  
 
10.10.3 
Management and Surveillance of Listeria during Study Participation 
In the event a subject experiences a persistent fever lasting 72 hours after receiving study 
treatment then the oral antibiotic regimen will be replaced by broad spectrum IV antibiotic 
treatment.  If symptoms consistent with sepsis occur close to ADXS11-001 administration or at 
any time after ADXS11-001 administration, immediate medical attention must be sought.  A 
microbial culture will be taken 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 subjects. 
 
All subjects will receive a 6-month course of an oral antibiotic regimen as a prophylactic measure 
approximately 72 hours following the completion of the last dose of ADXS11-001 treatment or at 
the time of study discontinuation.  This additional safety measure is intended to eradicate Lm from 
the body. 
 

 
 
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Lm surveillance monitoring will also be initiated following the completion of the last dose of 
ADXS11-001 treatment or at the time of study discontinuation. This monitoring will include 
obtaining a blood sample for CBC, comprehensive metabolic panel (CMP), including CRP and 
ESR, and blood cultures for the detection of Listeria.  Testing will be performed on all subjects 
who have received at least 1 dose of ADXS11-001 and occur 3 months(+/- 2 weeks), 6 months(+/- 
3 weeks), 9 months(+/- 1 Month), 12 months(+/- 1 Month),  and every 4 months(+/- 1 Month) for 
year 2 and year 3 postoperatively. 
 
Should a diagnosis of listeriosis be made at any point after treatment with ADXS11-001 is 
completed, immediate and intensive IV antibiotic treatment (ampicillin +/- gentamycin or other IV 
antibiotic regimen as indicated) is required.  An infectious disease consult should be obtained.  
Based on each individual subject’s case and at the discretion of the treating physician, the removal 
of any foreign medical object that has been present since treatment with ADXS11-001 was 
initiated may be warranted.  It is extremely important that the Investigator, his/her research staff, 
other healthcare providers involved in the care of the subject as well as each subject participating 
in this study are educated and made aware of the signs and symptoms of listeriosis and the 
potential for delayed listeremia/listeriosis.  Educational materials for the Investigator, research 
staff, health care providers and subjects will be prepared and educational training performed. 
 
10.10.4 
Potential for delayed/late Listeria infection: 
 
ADXS11-001 has been attenuated by ≥4 logs in comparison to the wild-type (wt)-Lm.  ADXS11-
001 is cleared by SCID mice lacking a functioning cellular immune system, as well as by gamma 
interferon knockout mice lacking adaptive immunity.  ADXS11-001 has been shown to be 
nonpathogenic in mouse models.  In a Phase 1 clinical study, in the absence of antibiotics, Lm 
was rapidly cleared from the blood. No Lm was detected in the blood, urine or feces of any 
subject beyond 48 hours post-dosing and at the highest dose of ADXS11-001 tested  (1 x 1010 
CFU)52.   
 
wt-Lm is known to form and persist within biofilms especially on medical devices despite 
antibiotic treatment.53 Although rare, medical device–related infections such as ventriculo-
peritoneal shunt infection, peritoneovenous shunt infection, and prosthetic joint infection have 
been reported.54-57 ADXS11-001 is highly sensitive to antibiotics such as ampicillin and 
trimethoprim/sulfamethoxazole which can be an effective treatment regimen for Listeria infection. 
However, to reduce the risk of ADXS11-001 persisting within a patient by attaching to the surface 
of a fixed medical device by establishing a biofilm, patients with indwelling medical devices 
require special consideration.  Therefore, subjects with implanted medical device(s) that pose a 
high risk for colonization and/or cannot be easily removed are excluded from this study. In 
addition, all subjects will receive a course of oral antibiotics beginning on Day 4 (approximately 
72 hours) after each dose of ADXS11-001 and for 6 months following the last dose of ADXS11-
001 to aid in the eradication of the bacteria. 
As of June 2016, approximately 290 subjects have received approximately 722 doses of 
ADXS11-001. During the course of treatment in this subject population, there has been one 
reported case of Grade 3 listeriosis. The subject was a 56 year old female who was enrolled in 

 
 
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November 2012 in Study GOG-0265.  During the course of her participation in the study, she 
suffered a motor vehicle accident which required multiple orthopedic surgeries involving the 
placement of hardware and a bone graft. After completing her participation in the study, she went 
on to receive multiple other treatments for her metastatic cervical cancer including an 
investigational PI3K inhibitor.  Two and a half years after completing her last administration of 
ADXS11-001, she presented to the hospital with mental confusion and a fever.  Blood cultures 
were positive for Lm. Subsequent analyses revealed that the isolate was essentially the same 
as ADXS11-001 but without the plasmid. The subject was admitted to the hospital and treated 
with IV Ampicillin.  She became afebrile and was discharged home three days after her 
admission.  Prior to her discharge a spinal tap and a CT of the brain were recommended but the 
subject refused. Two weeks later the subject presented with acute respiratory distress caused 
by her metastatic disease and died.  The investigator ruled that cause of death was due to 
disease progression (metastatic cervical cancer).  It is hypothesized that dosing of attenuated 
Lm soon after her bone graft may have resulted in biofilm formation, which could have protected 
the Lm from both the immune system and antibiotics.  At no time while the subject was on study 
or during the 2.5 years post-study did she show signs or symptoms of listeriosis.  The Lm isolate 
also remained highly susceptible to multiple antibiotics.  
Following recognition of this case of persistent Listeria colonization and delayed infection, new 
exclusion criteria and long-term monitoring provisions were added to this protocol to minimize 
the chance of this adverse event.  
Complete information on the toxicity profile can be found in the ADXS11-001 Investigator’s 
Brochure.  
11 TRANSORAL SURGERY FOR OROPHARYNGEAL CANCER 
1. Patients have previously been determined by an attending Head and Neck surgeon and 
the multidisciplinary tumor board at each site, to be eligible for transoral resection. 
2. Standard-of-care transoral surgery with intent to perform complete resection of the primary 
tumor will be performed according to our previously described methods50. In brief: surgery 
will include transoral robotic resection or transoral laser resection of the tumor with 
negative intraoperative frozen section margins; in selected cases it may be appropriate to 
remove the tumor with hand-held electrocautery under direct vision. Appropriate 
reconstruction will be performed at the time of tumor resection as deemed necessary by 
the operating surgeon.  
3. Selective neck dissection of levels II-IV will be performed routinely ipsilateral to the primary 
tonsillar tumors.  Bilateral selective neck dissection of levels II-IV will be performed for all 
tongue base tumors. Additional levels (i.e. I, V) will be performed at the discretion of the 
operating surgeon if indicated on the size and location of the primary tumor. N+ patients 
will undergo a simultaneous appropriate therapeutic neck dissection.  
 
11.1 POSTOPERATIVE ADJUVANT THERAPY AND CLINICAL FOLLOW-UP 
1. Adjuvant radiation therapy or chemoradiation will be given to appropriate patients based 
on preoperative and pathological risk factors as per standard-of-care. Participation in this 
trial will in no way alter the decision to provide post-surgical radiation or chemoradiation. 
While there is some leeway based on clinical judgment, standard criteria for adjuvant 
therapy include: positive surgical margin; lymphovascular invasion (LVI); perineural 

 
 
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invasion (PNI); extracapsular spread (ECS) of lymph node metastases or matted lymph 
nodes; low (level IV) cervical lymph nodes; >2 positive lymph nodes. These criteria are 
fairly standard across many institutions. If adjuvant therapy is indicated, therapy usually 
begins 4 to 6 weeks after surgical resection.  
2. Patients will undergo routine post-treatment clinical follow-up, which usually involves 
monthly visits for the first year and q2-3 month visits in the second year following 
treatment. Imaging is obtained at the discretion of the treatment team, but is generally 
obtained no less than q 3 months for the first 2 years after treatment.  
3. Assessment of disease status (no evidence of disease / NED; recurrent disease; second 
primary upper aerodigestive tumor; other second primary cancer) is performed by the 
attending surgeon at each follow-up appointment, and recorded in the electronic medical 
record (EMR).  
 
12.0 
SCHEDULE OF BLOOD AND SAMPLE COLLECTION 
 
12.1 TREATMENT GROUP 
1. The day of the first dose of vaccination will be considered “day 1”.  
2. Standard-of-care pre-treatment tumor biopsy will be performed in a timely fashion for 
those patients without a prior biopsy, whose prior biopsy is inadequate for clinical planning, 
or 
for 
whom 
prior 
biopsy 
material 
adequate 
for 
immunophenotyping 
by 
immunohistochemistry (IHC) is not available.  
3. Initial blood draw (Draw 1) will be obtained prior to the first vaccination usually during 
screening visit. 
4. Draw #2 will be performed on the day of the first vaccination (e.g. day 1) before vaccine 
infusion.  
5. Draw #3 will be performed on the day of the second vaccination (day 15) before vaccine 
infusion. 
6. Surgery, and harvest of tumor and TIL, will be performed on day 35 +/- 7 days following 
entry into the study and baseline blood draw. 
7. Draw #4 will be performed preoperatively, on the day of surgery prior to induction of 
anesthesia, or up to 72 hours prior to the surgery. 
8. Draw #5 will be performed 3 weeks (+/- 1 week) after surgery. 
9. Draw #6 will be performed 6 weeks (+/- 1 week) after surgery, before radiation. 
10. Draw #7 will be performed 3 months (+/- 3 weeks) post-surgery.  
11. Draw #8 will be performed 6 months (+/- 3 weeks) post-surgery. 
12. Draw #9 will be performed 12 months (+/- 4 weeks) post-surgery. 
 
12.1.1 LISTERIA SURVEILLANCE MONITORING BLOOD DRAW:  Up to 45 ml of additional 
blood will be collected for safety follow up testing as Listeria surveillance monitoring. It will 
include CBC, CMP, including CRP and ESR and blood cultures for the detection of Listeria. 

 
 
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Patients in the control group will NOT undergo additional blood draw or monitoring. These 
blood draws will be performed at 3 months(+/- 2 weeks), 6 months(+/- 3 weeks), 9 months(+/- 
1 Month), 12 months(+/- 1 Month),  and every 4 months(+/- 1 Month) for year 2 and year 3 as 
mentioned in schedule above. 
 
12.2 OBSERVATIONAL GROUP 
1. The day of screening will be considered “day 0”. Initial blood draw (Draw 1) will be obtained 
at screening. 
2. Standard-of-care pre-treatment tumor biopsy will be performed in a timely fashion for 
those patients without a prior biopsy, whose prior biopsy is inadequate for clinical planning, 
or 
for 
whom 
prior 
biopsy 
material 
adequate 
for 
immunophenotyping 
by 
immunohistochemistry (IHC) is not available.  
3. Draw # 2:  Observational patients will NOT undergo this blood draw. 
4. Draw # 3:  Observational patients will NOT undergo this blood draw. 
5. Draw #4 will be performed preoperatively, on the day of surgery prior to induction of 
anesthesia, or up to 72 hours prior to surgery. 
6. Draw #5 will be performed 3 weeks (+/- 1 week) after surgery. 
7. Draw #6 will be performed 6 weeks (+/- 1 week) after surgery, before radiation.  
8. Draw #7 will be performed 3 months (+/- 3 weeks) after surgery.  
9. Draw #8 will be performed 6 months (+/- 3 weeks) after surgery.   
10. Draw #9 will be performed 12 months (+/- 4 weeks) after surgery. 
 
12.3 COLLECTION AND PROCESSING OF PERIPHERAL BLOOD SAMPLES 
1. Baseline blood samples will be collected either immediately after consent or prior to the 
first vaccination. Samples will be collected at baseline, on the day of surgery (following 
two rounds of vaccination), and according to the schedule described above.  
2. At each collection, peripheral blood samples (eight 7mL tubes, 56 mL total) will be 
withdrawn by a clinical research coordinator, a medical assistant or a clinic nurse and 
promptly transported to the designated laboratory for processing. Immediately prior to 
drawing blood, the person in charge of the procedure will verify the subject‘s identity. 
Immediately after the blood has been collected, a label containing the appropriate subject 
identification number and the subject‘s initials is to be affixed to the vial. 
3. Serum will be obtained by centrifugation, and stored in 250uL aliquots at -80°C. Whole 
blood will be processed over a Ficoll gradient to obtain PBMC, and PBMC will be washed, 
counted, aliquotted and frozen in DMSO-containing freezing medium prior to long-term 
storage in liquid nitrogen. All tubes will bear self-adhesive labels that clearly identify the 
trial code, the patient number, the patient initials, and the visit number.  Sterile technique 
will be maintained throughout so that viable cells may be cultured and assayed after 
thawing.  
 

 
 
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12.4 COLLECTION AND PROCESSING OF TUMOR SPECIMENS 
1. Following resection, tumor specimens will be expeditiously transported to the pathology 
suite, where a pathologist will evaluate and identify the portion of the specimen in excess 
of that required for pathological analysis. 
2. A small piece will be flash-frozen and transported to each institution’s designated banking 
resource facility as is routinely performed for all head and neck cancer specimens.  
3. Where tumor size and quality permit, the remainder of the specimen will be transported 
on ice to the designated laboratory for harvesting tumor-infiltrating lymphocytes (TIL) 
according to a standard protocol. Briefly, after removal of fat, blood and necrotic areas, 
tumor tissue will be washed in RPMI-1640 containing 50 µg/ml gentamycin, and cut into 1 
mm 3 pieces in a petri dish covered with RPMI-1640. The sample is washed again with 
RPMI-1640 and upon transfer to flasks, dissociated using 0.05% collagenase type IV and 
0.02% DNase type I in RPMI-1640 supplemented with 5% (v/v) fetal calf serum and 
antibiotics. Tissues will then be dissociated for up to 4 h using a magnetic stirrer at 37°C. 
The digest will then be passed through 90 µm and 50 µm nylon mesh to remove clumps, 
and the filtrate washed in 2–3· mL medium followed by centrifugation at 350· g for 10 min 
and resuspension in 2 mL medium.  
4. PBMC will be washed, counted, aliquotted and frozen in DMSO-containing freezing 
medium prior to long-term storage in liquid nitrogen. All tubes will bear self-adhesive labels 
that clearly identify the trial code, the patient number, the patient initials, and the visit 
number.  Sterile technique will be maintained throughout so that viable cells may be 
cultured and assayed after thawing. 
 
12.5 IMMUNOPHENOTYPING AND CHARACTERIZATION OF HPV-SPECIFIC T CELL 
RESPONSES 
1. Following purification from whole blood or tumor, mononuclear cells will be cultured 48 
hours in the presence or absence of pools of 15-20-mer overlapping peptides 
encompassing the full-length HPV16 E6 and E7 antigens, or control (CMV, EBV and Flu 
virus) peptide mixtures.  
2. After 48 hrs of stimulation, an aliquot of supernatant from the culture will be harvested and 
frozen at -80°C for future studies of cytokine production.  
3. E6/E7-specific T cell responses will be determined by ELISPOT, flow-cytometry for 
intracellular IFN-γ staining, or other comparable method. In brief, staining for T cell surface 
markers (CD3, CD4, CD8) with labeled antibodies is performed prior to 
fixation/permeablization of cells. Fix/permed cells are then stained with labeled antibody 
to IFN-γ, a marker of activated cytotoxic T cells. Multicolor flow cytometric analysis is then 
performed on an LSR II flow cytometer.  
4. Additional flow cytometry staining panels to characterize NK cells (CD56), T cell activation 
and exhaustion markers (granzyme, perforin, CTLA-4, PD-1), regulatory T cell (CD127, 
CD25), and myeloid populations (CD11c, CD11b, CD33, HLA-DR) will be used to perform 
multi-dimensional immunophenotyping of effector and regulatory cell populations.   

 
 
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12.6 IMMUNOHISTOCHEMISTRY (IHC) AND MOLECULAR PROFILING OF TUMOR 
SPECIMENS 
1. Tumor specimens obtained during standard-of-care resection will be harvested for 
preparation of tissue microarrays (TMA) from formalin-fixed, paraffin-embedded (FFPE) tissue 
specimens, according to each site’s routine protocols. Histological slides which include tumor 
tissue and surrounding normal tissue from the tumor margin will be created with the help of the 
designated pathology facility at each site.  
2. Histological slides will be subjected to immunofluorescent staining and analysis. These 
data are quantified using image analysis instrumentation and software. This approach has 
allowed successful characterization and quantification of up to 5-7 antigens in single sections54. 
3. We will utilize a comprehensive panel of IHC markers including markers for myeloid 
cells; Treg (CD4/FOXP3); NK cells (CD56); and CD3+, CD4+ and CD8+ T cells.  Staining for 
these markers will be examined by multiplex immunofluorescence and their density in tumor 
quantitated by digital image analysis. Tumor infiltrating myeloid cells will be identified with the 
markers CD33 (myeloid-derived suppressor cells, MDSC), CD11b (MDSC, some macrophages, 
some DCs), and CD68 (macrophages), and neutrophils (CD66b).  
4. A portion of the tumor specimen will be flash frozen according to each site’s routine 
protocols, and cryopreserved for future molecular biology analyses of immune and cancer-related 
gene expression.  
 
13.0 CRITERIA FOR REMOVAL FROM STUDY 
Subjects may withdraw consent at any time for any reason or be discontinued from the trial at the 
discretion of the investigator, should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the sponsor/Study Chair if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons. 
 
Patients will be removed from the study, and notified of this fact, under the following 
circumstances:  
1. Failure to obtain at least one baseline blood draw.  
2. Failure to receive at least one vaccination (if in vaccine arm).  
3. The patient experiences a grade IV toxicity.  
If a patient is removed from the study or if the patient wishes to discontinue participation 
before all visits and monitoring are complete, the following will occur: 
- 
For patients in the treatment group, 3 years of Lm surveillance monitoring will be 
offered. 
- 
Patients in the treatment group will be provided with sufficient antibiotics to 
complete the 6 months of post-vaccine treatment as described above. 
 
 
 

 
 
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14.0  Concurrent Therapies and Procedures 
All prescription and nonprescription medication (excluding vitamins, nutritional supplements 
and hormone replacement therapy) taken by the subject from 30 days prior to screening 
and up to and including completion of the 3-year Lm surveillance period will be recorded in 
the medical record and on the eCRF.  Any addition, deletion, or change in the dose of 
these medications will also be recorded.  Generic names should be used to eliminate 
confusion that may result from trade names.  Protocol-mandated prophylactic medications, 
antibiotics and procedures administered/performed following the completion of study 
treatment, including during the 3-year Lm surveillance period, should also be captured in 
the eCRF. 
Study subjects should be reminded that acetaminophen should not be used for 
pretreatment prophylaxis associated with the foreseeable AEs related to the study 
treatment since this medication can interfere with treatment. 
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing trial.  If there is a clinical indication for one of these or other medications 
specifically prohibited during the trial, discontinuation from trial therapy may be required.  
The Investigator should discuss any questions regarding this with the Sponsor.  The final 
decision on any supportive therapy rests with the Investigator and/or the subject’s primary 
physician.  However, the decision to continue the subject’s on-trial therapy requires the 
mutual agreement of the Investigator, the Sponsor, and the subject. 
Subjects are prohibited from receiving the following therapies during the screening and 
treatment phases (including retreatment for post-complete response relapse) of this trial: 
• 
Anti-cancer systemic chemotherapy or biological therapy 
• 
Surgical treatment as per consultation with the sponsor 
• 
PI3K and TNFα inhibitors 
• 
Immunotherapy not specified in this protocol 
• 
Investigational agents other than ADXS11-001 
• 
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 trial treatment and while 
participating in the trial.  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 (e.g., Flu-Mist®) are live attenuated vaccines and are not 
allowed. 
• 
Acetaminophen is not to be used for premedication but may be used for 
supportive care measures. NSAIDs, such as naproxen and ibuprofen have 
been evaluated and are confirmed not to interfere with efficacy. 
Subjects who, in the assessment by the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the Investigator deems to be medically 
necessary. 

 
 
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15  Treatment Discontinuation: 
Surveillance monitoring for the detection of Lm will be initiated at the completion of study 
treatment according to the protocol or at the time of study discontinuation if earlier. This 
surveillance monitoring phase will consist of a 6 month course of oral antibiotics, obtaining a 
blood sample to monitor CBC, CMP, including CRP and ESR, and blood cultures at regular 
intervals. This testing will be performed on all subjects who have received at least one dose 
of ADXS11-001. It will occur at 3 months(+/- 3 weeks), 6 months(+/- 3 weeks), 9 
months(+/- 1 Month), 12 months(+/- 1 Month),  and every 4 months(+/- 1 Month) for 
2nd and  3rd year beginning after the last dose of study treatment.  If a persistent increase in 
CRP and/or ESR is observed with negative blood cultures for Listeria during this time the 
subject should be evaluated and treated, as appropriate, for another possible cause. In the 
event that a definite cause has not been identified then subjects must continue to be monitored 
closely, including another additional testing and a blood culture, for possible signs/symptoms 
of listeriosis.  This testing may be performed at the investigative site or at another acceptable 
location following consultation with the Sponsor. 
 
 
16.0 STATISTICAL CONSIDERATIONS 
We will employ the Simon’s two-stage design for the phase II clinical trials.  (Simon R. Optimal 
two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1-10.) This trial design 
maximizes the chances of detecting a true difference in the HPV-specific T cell frequencies in 
pre- and post-vaccination samples while minimizing the number of patients treated if there is no 
difference. We plan to enroll and vaccinate up to 22 HPV+ OPC patients. In parallel we also plan 
to enroll and collect samples from up to 10 un-vaccinated HPVOPC patients in the observational 
group.  
 
(a) 
Definition of primary outcome/endpoint: 
We will determine the rate of vaccine-induced T cell responses at the time of surgical resection. 
For evaluation of immune responses in the peripheral blood, for each patient, a vaccine-induced 
T cell response will be considered:  
1. Any post-vaccination E6- or E7-specific T cell response frequency (response to E6 or E7 
peptide pool, minus nonspecific background, measured by ELISPOT or intracellular 
cytokine staining) equal or greater to two times the initial pre-vaccination baseline 
response. Where two baseline measurements are available, the mean value will be used.  
2. When pre-vaccination E6/E7-specific T cell responses are not observed, any post-
vaccination response at least two-fold greater than the average value of nonspecific 
background (for ELISPOT, approx. 10-15 spots/well) will be considered a positive 
response.  
 
Toxicity will be scored using the NCI CTCAE 4.0 criteria, with any grade 3 or 4 toxicity considered 
as an adverse outcome. 
 

 
 
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(b) 
Definition of secondary outcomes/endpoints: 
1. We will determine the rate of vaccine-induced T cell responses at various time-points after 
surgery (3W, 6W, 3M, 6M, 12M). Otherwise as per the primary outcome/endpoint 
 
(c) 
Analytic plan for primary objective: 
For each patient, the baseline mean frequency +/- SD of peptide-specific IFN-γ and/or TNFα   
expressing T cells in the peripheral blood will be determined by averaging the results of 3 replicate 
assays. At each subsequent blood draw, the mean frequency +/- SD of IFN- γ positive T cells will 
be determined in an identical fashion, and vaccine-induced T cell responses determined as 
described above. The response to each peptide will be evaluated separately. While the ADXS 11-
001 vaccine contains the HPV E7 protein, cross-reactive responses to E6 and other HPV proteins 
can be observed following vaccination (personal communication, Robert Petit, Advaxis 
Pharmaceuticals) so we will monitor responses to E6, E7 and E2 peptides.  
The trial is designed to conclude that ADXS 11-001 vaccination is likely highly immunogenic and 
worth further investigation if the overall rate of vaccine-induced T cell responses is 75% or more. 
ADXS 11-001 vaccination will be deemed not worthy of further investigation if the overall rate of 
vaccine-induced T cell responses is less than 50%. 
For this trial, we propose a maximum sample size of 22 subjects, with 9 eligible subjects accrued 
in the first stage and 13 eligible subjects accrued in the second stage. One interim monitoring will 
be performed at the end of the first stage. The trial will be terminated early if it is evident that the 
T cell response rate is lower than the acceptable level. Since we do not yet know when the peak 
effect of vaccination will be, we will consider any responses at time of surgery or at 3 or 6 weeks 
after surgery to “count” as positive vaccine-induced T cell responses. If responses in five (5) or 
fewer patients are observed during the first stage, we will conclude that ADXS 11-001 vaccination 
does not merit continued investigation due to lack of immunologic efficacy. Otherwise accrual will 
continue until a total of 22 evaluable patients have been vaccinated and assessed for T cell 
response and toxicity.  
If after completion of accrual more than fourteen (14/22) patients have vaccine-induced T cell 
responses, we will conclude that ADXS 11-001 vaccination is sufficiently active to justify 
recommendation for future studies.  
(d) 
Analytic plan for secondary objectives: 
The frequency of ELISPOT-positive T cells in the peripheral blood will be determined as described 
above for each patient at baseline and at different time points after surgery (3W, 6W, 3M, 6M, 
12M). The average number of ELISPOT-positive T cells in the baseline and post-surgical samples 
will be compared, with p<0.05 by two-sided paired student’s T test considered a statistically 
significant difference.  
(e) 
Sample size justification:  
Using this design for the primary objective, the type-I error is 10%, and the power is 80.7%.  If the 
T cell response rate is indeed only 50%, then the probability to stop the trial at the end of first 
stage is 75%, and the expected sample size of 13.   
 
 

 
 
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17.0 DATA AND PROTOCOL MANAGEMENT  
The study chairperson, and IND holder Dr. Sikora, the site principal investigator and the site co-
investigator will be jointly responsible for the management of the protocol. All patients will be treated 
according to the recommendations of the institutional Head and Neck tumor board, and the standard-
of-care for their disease.  
 
17.1 DATA CONFIDENTIALITY  
All efforts will be made to ensure patient confidentiality and assurance of HIPAA compliance. 
Immediately after obtaining any specimens and microscopic images, subjects will be assigned a 
protocol specific unique code that will be used for all further data management. A list matching the 
patient medical record number to the protocol specific unique code will be kept in a locked cabinet in 
the office of the site PIs. The names of the patients will not be released to any outside organizations 
or to persons not involved with the study. They will not be revealed in written reports or publications 
detailing the research findings. All electronic data with patient identifying information will be 
maintained on password-protected computers at the respective institution. Use of portable media 
devices (external hard drives, USB drives, etc.) will be discouraged; if use of portable media devices 
is required for transfer of data, these devices are to be password protected and encrypted.  
 
17.2 PROTOCOL COMPLIANCE  
The primary research coordinator for this protocol will be responsible for accurate implementation of 
the protocol. Any deviations from the protocol will be reported to Dr. Sikora and the site PIs, who will 
determine the appropriate course of action. 
 
17.3 PROCEDURE TO OBTAIN INFORMED CONSENT 
Patients to undergo transoral surgical resection of oropharyngeal cancer will be identified by the study 
team at weekly tumor board conference, or on their initial visit to the clinic at each institution. 
Participation in the trial will be discussed with the patient by a study investigator or approved delegate 
prior to the initiation of treatment. Consent will be obtained by a study investigator or study 
coordinator. All patient confidentiality will be strictly maintained in accordance with HIPAA regulations.  
The principal investigators, all co-investigators, and study coordinators have taken the NIH approved 
Institutional Instructional Course for Studies Involving Human Tissues and must have completed 
Human Research Protection Education requirements by their institution. 
 
17.4 REPORTING REQUIREMENTS - ADVERSE EVENTS 
17.4.1 Adverse event (AE):  any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product or protocol-specified procedure, whether or not considered related 
to the medicinal product or protocol-specified procedure.  Any worsening (i.e., any clinically significant 
adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated 
with the use of study treatment (ADXS11-001 or Placebo) is also an AE.   
A serious AE (SAE) is any AE occurring at any dose or during any use of Advaxis’ product that: 

 
 
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• 
Results in death; 
• 
Is life threatening; 
• 
Results in persistent or significant disability/incapacity; 
• 
Results in or prolongs an existing inpatient hospitalization; 
• 
Is a congenital anomaly/birth defect; 
• 
Is a new cancer (that is not a condition of the study); 
• 
Is associated with an overdose; 
• 
Is another important medical event 
 
All adverse clinical experiences, whether observed by the investigator or reported by the patient, must 
be recorded, with details about the duration and intensity of each episode, the action taken with 
respect to the test drug, and the patient’s outcome.  The investigator must evaluate each adverse 
experience for its relationship to the test drug and for its seriousness.   
The PIs, co-Investigator, or a delegate will query the patient about adverse event (AE) at each follow-
up visit, and notify the PIs, who will be responsible for maintaining records of all AEs. Reporting will 
follow the descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. Any unanticipated adverse 
events resulting from this study will be reported to the study chair.  Additionally, unanticipated and 
SAEs should be reported to each site’s  institutional review boards as per their requirements and by 
the IND holder to the FDA according to the 21CFR312.32.  
Post 30 day AE assessment and for 3 year safety observation period: It is required that sites 
submit all SAEs that are thought to be possibly related to ADSX11-001 or which have any potential 
relationship or correlation to Listeria. This requirement is applicable for the ENTIRE Lm follow-up 
period of 3 years. All other SAEs or AEs not related to ADXS11-001 or with no relation to, suspicion 
of or possibility of being late listeriosis, do not need to be reported.                                   
To provide an enhanced opportunity to detect any adverse events, a 2 week delay (stagger) will be 
implemented between enrollment of patient #1 and #2 and patient #2 and #3. 
 
17.4.2 Expected adverse events include:  
1. Minor, self-limiting pain due to the injection.  
2. Minor, self-limiting, localized injection-site reaction <2cm and lasting for less than 72 hours. 
3. Fever (>100.9°F) with or without chills for up to 24 hours. 
4. Anemia, Headache, Vomiting and Nausea 
5. Tender cervical lymphadenopathy (possible).  
Please refer to the ADXS11-001 IB for a current list of expected adverse events. 
 
Progression of the cancer under study is not considered an AE unless it results in hospitalization or 
death. 
 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its 
individual symptoms.  The following information should be captured for all AEs:  onset and end dates, 
severity (grade of the event), Investigator’s opinion of the relationship to ADXS11-001 (see definitions 
below), treatment/action required for the AE, and information regarding resolution/outcome. 

 
 
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17.4.3 Reporting Abnormal Test Findings 
The criteria for determining whether an abnormal test finding should be reported as an AE are as 
follows: 
• 
Test result is associated with accompanying symptoms; and/or 
• 
Test result requires additional diagnostic testing or medical/surgical intervention: and/or 
• 
Test result leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatments, or other; and or 
• 
Test result is considered to be an AE by the Investigator or sponsor 
Merely repeating an abnormal test, in the absence of any of the above conditions does not constitute 
an AE.  An abnormal test result that is determined to be an error does not require reporting as an AE. 
 
17.4.4 Reporting Cytokine Release Syndrome 
As per NCI CTCAE v 4.03, CRS is defined as a disorder characterized by nausea, headache, 
tachycardia, hypotension, rash, and shortness of breath.  Subjects must have experienced ALL 
symptoms for an AE to be documented as CRS.  Individual symptoms associated with CRS should 
not be reported as CRS, but should be reported as separate AEs. 
 
17.5 Data/Safety Monitoring 
AE reporting and data and protocol monitoring will be performed in accordance with the protocol-
specific Data Monitoring and Reporting Plan and current Data Safety Monitoring Plan for investigator-
initiated Phase I and II studies in the Dan L Duncan Cancer Center at Baylor College of Medicine.  

 
 
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APPENDIX A 
ADXS11-001 Drug Ordering 
Drug Ordering and Distribution:  ADXS11-001 will be supplied by Advaxis and distributed 
by Almac Clinical Services LLC.  No supplies will be shipped to any site until regulatory 
approval has been obtained.  There will NOT be an initial drug supply forwarded to all 
investigational sites until initial regulatory approval. 
 
Initial and Subsequent Requests:  The designated person(s) from each participating 
hospital will complete the Drug Order Request Form and email the completed form to Almac.  
Study drug is not patient specific and you may order multiple vials of study drug to 
accommodate more than one patient depending upon the enrollment expectations at your site 
and storage capacity at -80 ± 10°C. 
 
ADXS11-001 will be shipped from Almac Clinical Services directly to the institution. Shipments 
will be made Monday through Thursday for Tuesday through Friday delivery per the table 
below.  To ensure ample time for delivery, drug requests must be received by Almac before 
12:00 pm Eastern Standard Time (EST) Monday through Wednesday.  If the drug request is 
received prior to 12 noon, that will be considered Day 1.  Study drug will be shipped Day 2 to 
arrive on site Day 3 before 10:30 am local time. Receipt and dispensing of trial medication 
must be recorded by an authorized person at the trial site. 
 
Orders in (by 12 PM 
EST) 
Shipment Out 
Expected Delivery 
Monday 
Tuesday 
Wednesday 
Tuesday 
Wednesday 
Thursday 
Wednesday 
Thursday 
Friday 
Thursday 
Monday 
Tuesday 
Friday 
Monday 
Tuesday 
EST = Eastern Standard Time 
 
Complete and email the Drug Reorder Request Form to: 
ATTN: 
palogistics.clinicalservices@almacgroup.com 
CC: 
Larry.haines@almacgroup.com 
logistics@advaxis.com 
 
Cold Chain Verification:  Cold chain verification must be completed immediately before 
unpacking the shipper, by carefully following the instructions below: 
 
 
 

 
 
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TempTale USB4 Temperature Recorder Review Instructions 
 
Stopping the Monitor: 
On receipt of the shipment, the TempTale USB4 temperature recorder should be stopped.  For 
this the RED stop button is held down firmly for 3 seconds.  A hexagonal “STOP” icon 
appears in the upper right hand corner of the display. 
Alarm: 
A small blinking “BELL” icon 
 is on the display after the device has been stopped.  This 
means that during the transport a significant temperature excursion occurred.  Please follow 
steps 1-6. 
1) Plug the USB cable into your computer. 
2) Copy both files from the USB device into an email. 
3) Specify the subject header with Protocol Name, Site Name/No. and Shipment No.  
4) Please send an e-mail with both attachments to Almac and Advaxis via the following e-
mail addresses: 
• 
coldchainteampa@almacgroup.com 
• 
logistics@advaxis.com 
5) The medication contained in this shipment must not be dispensed to patients until a 
positive written feedback from Advaxis is available. 
6) Please store the affected medication separately and wait until confirmation of supply 
usability is received. 
 
No Alarm: 
 
If the device has been stopped and no blinking “BELL” icon is visible, verification that the 
medication was shipped under good conditions is complete.  No further actions from your side 
are necessary.  Please discard the temperature logger.  You can use the medication 
immediately. 
Display 
Stop Button 
USB Adapter & 
Cable 

 
 
 V 1 1. 2 (1/ 9/ 2 0 ) 
 
 
 
P a g e 4 9  of 5 0  
 
N o st u d y dr u g s h o ul d b e a d mi ni st er e d t o  a n y p ati e nt s u nl e s s t h e T e m p T al e U S B 4 h a s 
b e e n r e vi e w e d a n d t h e s hi p m e nt h a s b e e n v erifi e d or a ut h ori z e d f or cli ni c al u s e.  
 
F or q u e sti o n s a b o ut T e m p T al e U S B 4 a n d dr u g s hi p m e nt s, pl e a s e e -m ail t h e f oll o wi n g:  
Al m ac: pal o gistics.cli nicalser vices @al mac gr o u p.c o m  
C C:  
larr y. hai nes @al mac gr o u p.c o m 
  
l o gistics @a d va xis.c o m 
 
Dr u g A c c o u nt a bilit y :  All st u d y dr u g m u st b e a c c o u nt e d f or b y u si n g t h e N CI Dr u g 
A c c o u nt a bilit y F or m d uri n g t h e c o ur s e of t hi s st u d y. T h e p h ar m a ci st or q u alifi e d r e s e ar c h st aff 
m e m b er will m ai nt ai n i n v e nt or y r e c or d s.  T h e r e c or d s will i n cl u d e d et ail s of m at eri al s r e c ei v e d, 
t h e d at e di s p e n s e d, t h e p ati e nt i d e ntifi c ati o n n u m b er a n d i niti al s of p ati e nt r e c ei vi n g t h e d o s e , 
a n d d o c u m e nt ati o n of dr u g d e str u cti o n f oll o wi n g n otifi c ati o n fr o m t h e S p o n s or or 
c o m pl eti o n/t er mi n ati o n of t h e st u d y.  R e c ei pt a n d di s p e n si n g of tri al m e di c ati o n m u st b e 
r ec or d e d b y a n a ut h ori z e d p er s o n at t h e tri al sit e.  It i s t h e I n v e sti g at or’ s r e s p o n si bilit y t o 
arr a n g e f or di s p o s al of all e m pt y c o nt ai n er s, pr o vi d e d t h at pr o c e d ur e s f or pr o p er di s p o s al h a v e 
b e e n e st a bli s h e d a c c or di n g t o a p pli c a bl e f e d er al, st at e, l o c al a n d  i n stit uti o n al g ui d eli n e s a n d 
pr o c e d ur e s, a n d pr o vi d e d t h at a p pr o pri at e r e c or d s of di s p o s al ar e k e pt.  
 
Dr u g D e str u cti o n a n d R et ur n :  O p e n e d a n d u n o p e n e d vi al s  c a n b e d e str o y e d a c c or di n g t o t h e 
sit e’ s g ui d eli n e s f or Bi o h a z ar d W a st e Di s p o s al or b y u si n g t h e st e p s s h o w n b el o w f or A D X S 1 1 -
0 0 1 d e str u cti o n.   
 
T h e u s e d or u n u s e d vi al s of A D X S 1 1 -0 0 1 c a n b e tr e at e d wit h a 1 0 % bl e a c h s ol uti o n f or 
di si nf e cti o n.  U s e a 1 0 % s ol uti o n of Cl or o x  ( or a n y si milar c o m m ercial c hlorin e ble a c h s olutio n 
c o nt ai ni n g 5. 2 5 % s o di u m h y p o c hl orit e ( N a Cl O) f or di si nf e cti o n . 
 
1.  Tr e at u n o p e n e d or o p e n e d vi al s( s) wit h a mi ni m u m v ol u m e of 0. 2 5 m L of bl e a c h s ol uti o n 
t o st erili z e it s c o nt e nt s. 
2.  E m pt y t h e di si nf e ct e d c h e mi c al s ol uti o n i n dr ai n, r u n w at er t o r e m o v e r e si d u al m at eri al s 
fr o m dr ai n a n d di s c ar d e m pt y vi al s i nt o d e si g n at e d bi o h a z ar d o u s w a st e c o nt ai n er, a s 
a p pli c a bl e.  
3.  T h e r e si d u al I V b a g s or ot h er c o m p o n e nt s u s e d f or pr e p ari n g t h e dr u g pr o d u ct s h o ul d 
al s o b e i n a cti v at e d wit h bl e a c h a n d di s c ar d e d i n si mil ar m a n n er a s e x pl ai n e d i n st e p s 1 
a n d 2.  
 
If A D X S 1 1-0 0 1 i s d e str o y e d at t h e sit e, it will b e t h e i n v e sti g at or’ s r e s p o n si bilit y t o e n s ur e t h at 
pr o c e d ur e s f or pr o p er di s p o s al h a v e b e e n e st a bli s h e d a c c or di n g t o a p pli c a bl e r e g ul ati o n s, 
g ui d eli n e s, a n d i n stit uti o n al pr o c e d ur e s a n d t h at:  
•  
Br U O G h a s b e e n al ert e d t o dr u g d e str u cti o n a n d h a s b e e n s e nt h o s pit al d e str u cti o n 
p oli c y  
•  
writt e n a ut h ori z ati o n f or di s p o s al/ d e str u cti o n h a s b e e n gr a nt e d b y A d v a xi s  
•  
arr a n g e m e nt s h a v e b e e n m a d e f or t h e di s p o s al  
•  
a p pr o pri at e r e c or d s of t h e di s p o s al h a v e b e e n d o c u m e nt e d  
 
A s e p ar at e N CI Dr u g A c c o u nt a bilit y F or m m u st b e c o m pl et e d f or Dr u g D e str u cti o n . 

 
 
 V11.2 (1/9/20) 
 
 
 
Page 50 of 50 
 
 
Accidental Spills:  All accidental spills shall be handled in compliance with applicable site safety 
procedures or following the guidance below: 
1. In the event there is an accidental spill of ADXS11-001, isolate the area and notify others 
in the vicinity. 
2. Put on appropriate personal protective equipment (PPE) if not already worn (e.g. gown 
or lab coat, gloves and loose fitting mask with eye shield or goggles). 
3. Remove any broken glass or sharps and place them into sharps container. 
4. Place paper tower over the spill. 
5. Saturate the paper-towel(s) with bleach starting at the outside of the spill and working 
towards the center. Allow the 10% bleach solution to remain on area for approximately 
10 min. 
6. Dispose the paper towel(s) in a biohazardous waste container. 
7. Clean the remaining disinfectant with additional paper towels, as needed. 
8. Discard all materials including PPEs, in the designated biohazardous waste container(s). 
9. Inform the Principal Investigator (PI) and other appropriate personnel, e.g. Research 
Manager, Pharmacy Manager. 
 
Exposure to ADXS11-001:  All exposure incidences shall be handled in compliance with 
applicable site safety procedures or following the guidance below: 
1. In the event of an accidental exposure, remove and dispose of contaminated PPEs or 
clothing into the designated biohazardous waste containers. 
a. For skin contamination:  thoroughly wash the affected area immediately with soap 
and water. 
b. For needle stick injury:  wash the affected area thoroughly with soap and water and 
cover the area with a sterile gauze dressing.  Notify the PI who will determine 
appropriate medical actions to be taken. 
2. For eye contamination: immediately and thoroughly rinse the affected area for up to 15 
minutes using an eyewash; making the water flow across the affected eye from the nose 
to the outer corner of the eye. If only one eye is contaminated, avoid contaminating the 
other eye (position your head so the affected eye must be below the other eye). Notify PI 
who will determine appropriate medical actions to be taken. 
 
It will be the investigator’s responsibility to ensure that procedures for proper disposal have 
been established according to applicable regulations, guidelines, and institutional procedures 
and that: 
• 
the coordinating institution has been alerted to drug destruction and has been sent 
hospital destruction policy, if applicable 
• 
arrangements have been made for the disposal 
• 
appropriate records of the disposal have been documented 
 
A separate (NCI) Drug Accountability Form must be completed for drug destruction.