ADXS11 -001 is bioengineered to secrete an antigen- adjuvant fusion protein (tLLO -HPV-E7) consisting of a truncated fragment of the list eriolysin 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 HPV -E7-tLLO fusion protein. This peptide, along with other Lm peptides, is very rapidly ubiquitinated and transported to the proteasome where the peptides are broken down and cross -presented through major histocompatibility complex (MHC) Class 1 and Class 2 pathways. This cross -presentation, in immunologic context of responding to a “perceived” acute infection, stimulates the development of adaptive immunity culminating in HPV -specific effector T- cells that can infiltrate into the tumor microenvironment (TME) and destroy tumor cells immunologically . Advaxi s 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 targe t-specific T -cell immunity. High avidity T -cells are generated where possible, V11.2 (1/9/20 ) Page 8 of 50 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 partiall y 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 PROFIL E 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 . V11.2 (1/9/20 ) Page 9 of 50 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 surv ivor, 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 treatme nt 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 p atient 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. V11.2 (1/9/20 ) Page 10 of 50 13. The p atient 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. Patient s who are receiving or may receive future treatment with PI3K or TNF α 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 lig ation 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 V11.2 (1/9/20 ) Page 11 of 50 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 patient s with the same characteristics who will undergo transoral resection without vaccination. We will collect, process and store tumor specim ens, 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. V11.2 (1/9/20 ) Page 12 of 50 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. V11.2 (1/9/20 ) Page 13 of 50 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 d ifferential 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 V11.2 (1/9/20 ) Page 14 of 50 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 ca ll 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 AD XS11 -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 Stan dard o f care test *14 To be done within 10 -14 days prior to vaccine 1 V11.2 (1/9/20 ) Page 15 of 50 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 gro up will not undergo research blood Draw #2 and #3. V11.2 (1/9/20 ) Page 16 of 50 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 m edications , 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 oncog enic subtypes . HPV testing will be performed in the designated laboratory at each site. The results of PCR testing will be reported to the patient s as a research, not a clinical procedure. V11.2 (1/9/20 ) Page 17 of 50 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 a n 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 t o 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: ADXS 11-001 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 ) Page 18 of 50 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 i nfusion 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 Edition 59 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 recombi ne 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 funct ion. Even though ADXS11 -001 is non- pathogenic, all Lm species are classified as BSL- 2 according to the BMBL 5 th Edition. Universal precautions and institutional guidelines should be used when handling investigational drugs and human specimens. Except fo r 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. V11.2 (1/9/20 ) 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 faci lities 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 wi th 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 infusi on 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, r oom 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 1x10 9 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 pl aced 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 V11.2 (1/9/20 ) Page 21 of 50 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 moderat e-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. V11.2 (1/9/20 ) Page 22 of 50 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 moni tor 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. V11.2 (1/9/20 ) Page 23 of 50 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 Sectio n 4.6 (Supportive Care). 10.9 MAJOR AND MINOR SURGERIES AND ADXS11 -001 T REATMENT : 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.