Clinical trial NCT01671488
Conditions: Anal Cancer
Keywords: Anal Cancer Mitomycin 5-Fluorouracil 5-FU IMRT ADXS11-001
Sponsor: Brown University
Start date: 2013-02-01; Completion date: 2018-02-01
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to study the safety and effectiveness of ADXS11-001 when combined with standard chemotherapy and radiation treatment for anal cancer. ADXS11-001 is an investigational agent that is not approved by the FDA to treat anal cancer or any other cancer.

Detailed description:
Novel treatments are needed in anal cancer. An important percentage of patients with locally advanced anal cancer will have persistent loco-regional disease or develop systemic metastases. Virtually all cases of anal cancer are related to infection by HPV. Anal cancer cells infected with HPV have the tumor associated antigen HPV E7. ADXS11-001 causes antigen presenting cells to be stimulated to facilitate immune cells to attack cancer cells expressing HPV E7. ADXS11-001, at the phase II dose of 1x109 CFU, has been shown to be safe in patients with advanced cervical cancer which also is caused by HPV infection. Anti-tumor activity and safety have been demonstrated in cervical cancer to single agent ADXS11-001 and the combination of ADXS11-001 and cisplatin chemotherapy. Data presented at ASCO 2012 ADXS11-001 is currently being evaluated in women in the United States with cervical intraepithelial neoplasia. Radiation may augment the activity of ADXS11-001 increasing the exposure of tumor related antigens thereby increasing the chance for loco-regional disease eradication and preventing systemic recurrence. Therefore, ADXS11-001 may increase complete response, prevent recurrence disease and increase disease-free and overall survival in anal cancer. This protocol will develop sufficient preliminary safety and efficacy data to facilitate the investigation of ADXS11-001 in anal cancer within "NRG", the newly formed cooperative group based on the merger of the RTOG, NSABP and GOG.

As described above, Phase I studies and preliminary data from phase II studies have demonstrated that ADXS11-001, 1x109 CFU, can be safely administered as a single agent and in combination with chemotherapy. For example in over 200 patients treated at the dose of 1x109CFU there have been no cases of severe listeria bacteremia or grade 3 cardiopulmonary toxicity. However, since ADXS11-001 has not previously been administered with radiation, the primary objective of this study will be to establish the safety of the addition of ADXS11-001 to chemoradiation for anal cancer. The following schedules will be assessed.

• Treatment Schedule: The first dose will be given 10-14 days prior to the initiation of chemoradiation. The 2nd-4th dosages of ADXS11-001will not be until after completion of all chemoradiation. The second dosage of ADXS11-001 will not be administered until a minimum of 10 days after completion of chemoradiation, ANC \> 1,000 cells/mm3, serum creatinine \< 1.5 mg/dl and all toxicities from chemoradiation have resolved to grade 2 or less. The subsequent third and fourth treatment with of ADXS11 will be administered at 28 day intervals. This will provide the needed safety data to evaluate Treatment Schedule #2.

Standard treatment with mitomycin, 5-FU and radiation for anal cancer has substantial toxicity. In RTOG 9811, 74% of patients had grade 3/4 nonhematologic toxicity and 61% of patients had grade 3 or grade 4 hematologic toxicity from this regimen. Therefore, the toxicities of standard chemoradiation with mitomycin, 5-FU and radiation are well above the conventionally accepted parameters in a phase I study even prior to adding ADXS11-001. However, it is critical that the addition of ADXS-11-001 does not compromise the delivery of potentially curative standard chemoradiation for anal cancer.

Arms: arm 1: The first dose will be given 10-14 days prior to the initiation of chemoradiation.

Patient will then receive 5-FU: 1 gm/m2/day x 96 hours beginning on day 1-4 and day 29-32 + 7 days and Mitomycin: 10 mg/m2, day 1 and 29 with IMRT radiation: 54 Gy in 30 fractions at 1.8 Gy per fraction.

The 2-4th dosages of ADXS11-001 will not be until after completion of all chemoradiation. The second dosage of ADXS11-001 will not be administered until a minimum of 10 days after completion of chemoradiation. The subsequent third and fourth treatment with of ADXS11 will be administered at 28 day intervals.
Interventions: intervention 1: Treatment intervention 2: 5FU intervention 3: Mitomycin intervention 4: IMRT
Intervention descriptions: intervention 1: ADXS11-001 will be given at a dose of 1x109 cfu intravenously once every 28 days for 4 total doses. All 4 doses of ADXS11-001 will be 1x109 cfu. intervention 2: 1 gm/m2/day x 96 hours beginning on day 1-4 and day 29-32 + 7 days intervention 3: 10 mg/m2, day 1 and 29 (day 29 can be + 7 days) intervention 4: 54 Gy in 30 fractions at 1.8 Gy per fraction.

Protocol documents:
Prot_SAP_ICF_000.pdf: 
3/28/16/pg. 1 
 
BrUOG 276 
 
 
 
 
 
 
 
 
IND #15057 
 
A Phase I/II Evaluation of ADXS11-001, Mitomycin, 
5-fluorouracil (5-FU) and IMRT for Anal Cancer 
 
Howard Safran, MD 
The Brown University Oncology Research Group 
 
 
Christopher Crane, MD 
M.D. Anderson Cancer Center 
 
Lisa Kachnic, MD 
Boston Medical Center 
 
Evgeny Yakirevich, MD 
The Brown University Oncology Research Group 
 
Coordinating Center 
Kayla Rosati 
233 Richmond Street Box G-R 001 
Providence, Rhode Island 02903 
Phone: (401) 863-3000 
Fax: (401) 863-3820 
Email: Kayla_Rosati@brown.edu 
 
Brown University Oncology Research Group 
Supported in part by Farrah Fawcett Foundation 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the 
extent necessary to obtain informed consent, may not be disclosed to another party unless law 
or regulations require such disclosure.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them. 
Protocol 8/22/12, Amendment #1 11/19/12, Amendment #2 1/14/13, Amendment #3 4/4/13, Amendment #4 8/14/2013, 
Amendment # 5 10/23/13, Amendment # 6 1/23/14, Amendment #7 4/1/14, Amendment # 8 5/29/14, Amendment # 9 6/13/14 
Amendment #10 6/30/14, Amendment # 11 7/15/14, version 2 to use 8/14/14, Amendment # 12 9/10/14, Amendment # 13 
2/13/15, Amendment # 14 6/1/15, Amendment #15 8/11/15, Amendment # 16 3/28/16


3/28/16/pg. 2 
 
TABLE OF CONTENTS 
Section  
 
 
 
 
 
 
 
 
Page 
1.0 
OBJECTIVES  
 
 
 
 
 
 
3 
2.0 
BACKGROUND 
 
 
 
 
 
 
3 
3.0 
PATIENT ELIGIBILITY 
 
 
 
 
 
16 
 
 
4.0 
TREATMENT 
 
 
 
 
 
 
18 
5.0 
TOXICITIES, ASSESSMENT, AND DOSE MODIFICATIONS 
32 
                                                     
6.0 
SCHEDULE OF EVALUATIONS / STUDY CALENDAR 
 
35 
                          
7.0      RECURRENCE ASSESSMENT 
 
 
 
 
38 
 
 
8.0 
PATIENT REGISTRATION  
 
 
 
 
39 
9.0 
PHARMACEUTICAL INFORMATION                                           
39 
10.0 
AGENT ACCOUNTABILITY     
 
 
 
 
48 
11.0 
ADVERSE DRUG REACTION REPORTING 
 
 
49 
 
12.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
54 
13.0 
FOLLOW UP    
 
 
 
 
 
 
55 
   
14.0 
REGULATORY CONSIDERATIONS   
 
                          55 
15.0 
DATA MONITORING/QUALITY ASSURANCE/ 
 
 
57 
RECORD RETENTION 
 
 
 
 
 
 
 
16.0 
DATA SAFETY AND MONITORING BOARDS 
 
 
59 
 
17.0 
STATISTICAL CONSIDERATIONS  
 
 
    
59 
18.0 
REFERENCES                                                                        
61 
 
APPENDIX SECTION: 
 
 
 
 
 
APPENDIX A INFORMED CONSENT 
 
 
 
 
 
APPENDIX B ELIGIBILITY CHECKLIST  
 
 
APPENDIX C COMMON TOXICITY CRITERIA  
 
 
APPENDIX D ECOG PERFORMANCE STATUS   
 
 
APPENDIX E CASE REPORT FORMS 
 
APPENDIX F ADVERSE EVENT FORM: OBA FORM


3/28/16/pg. 3 
 
1.0  OBJECTIVES  
1.1 Primary  Objectives 
1.1.1 To evaluate the safety of the addition of ADXS11-001 to standard chemoradiation for patients with 
anal cancer. 
1.1.2 To evaluate the 6-month clinical complete response rate for patients with anal cancer treated with 
ADXS11-001 mitomycin, 5-FU and IMRT. 
 
1.2 Secondary Objectives :  
1.2.1 To evaluate progression-free and overall survival for patients with anal cancer treated with 
ADXS11-001, mitomycin, 5-FU and IMRT. 
1.2.2 To correlate HPV type with 6-month clinical complete response, and progression-free and overall 
survival, after treatment with ADXS11-001 and standard chemoradiation.  
 
2.0  BACKGROUND  
2.1 Anal Cancer:  
There are about 5,290 new cases of anal cancer each year. A higher incidence is associated with female 
gender, infection with human papillomavirus (HPV), lifetime number of sexual partners, anal intercourse, 
and infection with human immunodeficiency virus.1 Substantial progress has been made in the 
management of anal cancer.2-4 Randomized trials have shown that chemoradiation improves local control 
compared with radiotherapy alone, and that radiotherapy and concurrent 5-fluorouracil (5-FU) and 
mitomycin-C (MMC) improves disease-free survival and colostomy-free survival, compared with 
radiotherapy and concurrent 5-FU.2-4 The RTOG 98-11 trial demonstrated that patients treated with 
induction 5-FU and cisplatin followed by concurrent 5-FU/cisplatin and radiotherapy have a higher 
colostomy rate than patients treated with concurrent 5-FU/MMC and conventional radiotherapy.5 
Preliminary results from the UK ACT II study show that maintenance chemotherapy with 5-FU/cisplatin 
is not effective after chemoradiation at decreasing cancer recurrence.6  
 
Need for Further Improvement in Outcomes:  
While many patients treated with chemoradiation for anal canal cancer have adequate outcomes, there 
remains considerable room for improvement.5,7,8 In RTOG 98-11, patients in the radiotherapy and 
concurrent 5-FU/MMC arm had a 3-year disease-free survival rate of only 68%.5  Five year outcomes of 
the RTOG 98-11 trial per individual tumor and nodal stage, presented at 2011 ASCO GI, demonstrated 
that disease-free survival is 40% or less for patients with T4N0 and/or node positive disease.8 An M.D. 
Anderson retrospective study showed that higher T stage (P = 0.023) and higher N stage (P = 0.030) 
independently predicted for a higher rate of locoregional failure.7 The 3-year rate of locoregional control 
was 90% for T1/Tx, 86% for T2, 77% for T3 and 63% for T4 tumors. Therefore, trials examining more 
aggressive and innovative regimens in anal canal cancer are warranted in patients at high-risk for 
treatment failure in order to improve outcomes.   
 
HPV and Anal Cancer: 
There is a close association between human papilloma virus and squamous cell cancer (SCC) of the anal 
canal.9-11 HPV DNA has been isolated from 80 to 100 percent of in situ and invasive SCCs of the anus.9-11 
While multiple HPV types can be found in the anal canal, the subgroup that appears to be the most 
common high-risk type is HPV subtype 16 (HPV-16) which is present in approximately 80% of anal 
cancer cases.12,13 Expression of viral E6 and E7 oncoproteins inactivate the tumor-suppressor proteins p53 
and the retinoblastoma protein (pRb), respectively.14,15 In SCC of the head and neck, the RTOG has 
established a strong relationship between tumor HPV status, as determined by in situ hybridization, and 
survival following chemoradiation (Ang 2010).  The RTOG has also correlated the expression of p16, an 
established biomarker for the function of the HPV E7 oncoprotein, to outcome after treatment for head 
and neck cancer.16 
 
 
 


3/28/16/pg. 4 
 
2.2 
HPV Vaccines  
Similar to anal cancer, squamous cell carcinoma of the cervix is largely the result of persistent infections 
with high-risk types of human papillomavirus.17  Approximately 95-99% of cervical cancers have 
detectable amounts of HPV DNA.17  Squamous cell carcinoma of the cervix requires the constitutive 
expression of the HPV oncoproteins E6 and E7.18  Thus, the E6 and E7 antigens have been an intense 
focus of cancer immunotherapies using a variety of vaccine vectors. Because of the intra-cellular 
localization of these antigens, these therapies are mostly directed at cellular immune responses.  The 
ability to deliver antigen to the cytosolic compartment of APCs in order to develop HLA class I 
presentation to induce CD8+ cytotoxic T cell responses is widely believed to be necessary for developing 
an effective therapeutic anti-tumor vaccine.19 
 
The literature provides many references to support the idea that many HPV species may respond to 
therapeutic agents based upon HPV-16 E7.20-22 A phase II study, conducted by the New York Phase II 
Consortium (an NCI-sponsored consortium), immunized 31 healthy women with biopsy-proven Cervical 
Intraepithelial Neoplasia (CIN) III with three, monthly subcutaneous vaccinations with 500 mcg of SGN-
00101 [Heat Shock Fusion Protein-Based Immunotherapy (HspE7)].  Of the 31 evaluable patients, 32% 
(10/31) had a complete pathologic response; 39% (12/31) had a partial response and 29% (9/31) had 
stable disease. The overall response rate was 71% (22/31, 95% C.I.=55-87%). No patients 
progressed.  Fifty-five percent (17/31) were HPV-16 positive prior to vaccination and one patient had 
HPV-16 subsequently detected. These results suggest many cervical cancer patients (not just those who 
are HPV-16 positive) could potentially benefit from the vaccine targeted at HPV-16 E7. Further, it 
supports the idea that HPV epitopes are sufficient similar to allow efficacy in other HPV types. Research 
completed by Nventa, formerly Stressgen, reports extremely high efficacy using the HPV-16 E7 antigen 
even in non-HPV-16 positive patients; which demonstrates the antigen has immuno-therapeutic activity 
across HPV types.23  Davidson et al. reported cross reactivity to the E7 antigen and responses in patients 
with other HPV types in a trial of a vaccinia based HPV-16 E7 vector tested in the clinical treatment of 
high grade vulval intraepithelial neoplasia (VIN).24  Luxton et al, reported that 22% of responding women 
treated with HPV-16 E7 peptide epitopes for the treatment of cervical dysplasia or neoplasia were 
negative for HPV-16 DNA.25  Slevy et al. reported that B cell epitopes of HPV-16 E7 are cross reactive 
with HPV-18.26  Krchnak et al, found while investigating HPV-16 E7 epitopes that of the 9 overlapping 
peptides that were made to map the immunogenic domains, some epitopes were type-specific and others 
were cross reactive with other HPV types.27  Additional support for the cross reactivity of HPV-16 E7 
with other HPV types has been demonstrated in human HLA-A2 transgenic mice.28  It further appears that 
certain HPV-16 E7 epitopes are conserved across genera, as Nilges et al demonstrated that “…cross-
reactivity represents the inherent nature of the T-cell repertoire” with cross reactivity between HPV-16 E7 
and Coronovirus protein OC43 NS2.29  
 
External Beam Radiation Therapy May Enhance Vaccines: Tumor cells by themselves do not express 
the complete repertoire of molecules necessary to render them maximally susceptible to immune 
responses induced either endogenously or by immunotherapy.30 Evolving knowledge on the ‘abscopal 
effect’ (also called the 'bystander effect'), wherein local radiation has cell mediated antitumor effect on 
tumors distant from the sites of radiation, has created interest in radiation as a possible modulating agent 
for immune responses towards tumor cells. Radiation induces expression of molecules that add specificity 
to tumor cell responses induced by immunotherapy. Potentially, such effects can also be exploited at 
tumor sites distant from radiation sites. For example, dead tumor cells from radiation provide signals for 
dendritic cell activation.31 Radiation damage causes phenotypic changes such as upregulation of FAS,32 
MHC Class-I,33  and expression of calreticulin34 on tumor cell surface. In murine models of metastatic 
renal cell cancer, combination therapy with radiation and IL-2 achieved greater tumor reduction than 
either modality alone.35 Similarly, addition of 8Gy of local radiation to therapeutic vaccination for CEA 
expressing subcutaneous murine tumors increased immune response.36 In a phase I study by Chi et al, the 
combination of 8 Gy of radiation and intratumoral injection of autologous immature dendritic cells in 
refractory hepatoma was well tolerated.37 A phase II study by Okawa et al assigned women with 
carcinoma cervix to 15-30Gy of radiation with or without an immune adjuvant LC9018 (a bacterial 


3/28/16/pg. 5 
 
extract).38 The study showed a significant effect on tumor reduction with the combination compared to 
XRT alone.  Gulley et al randomized men with localized prostate cancer to XRT with or without vaccinia-
based prostate cancer vaccine.39 Thirteen of 17 patients in the combination treatment arm had increases in 
PSA specific T cells of at least 3-fold.40 Slovin et al reported a phase I/II trial of ipilimumab  alone and in 
combination with radiation in both chemotherapy naïve and post-chemotherapy, hormone refractory 
prostate cancer patients.41 Preliminary results show no increase in immune related adverse events in all 
subgroups when compared to ipilimumab in melanoma. Addition of 10mg/kg ipilimumab to prostate 
radiation was well tolerated.40,41  
 
2.3 
Recombinant Listeria monocytogenes (Lm) as a Vaccine Vector 
The advantages that Listeria monocytogenes possesses as a vaccine vector are rooted in its biology.  It is a 
beta hemolytic gram-positive facultative intracellular bacterium that has been used to study cell mediated 
immunity for decades.42  Listeria preferentially infects APC, and unlike other intracellular bacteria, 
escapes into the cytoplasm of the host cell by disrupting the phagosomal membrane.  Since Listeria is a 
gram positive organism it does not release endotoxin.  Humoral immunity does not play a major role in 
combating Listerial infections because Listeria quickly leaves the circulation becoming an intracellular 
infection, and because it replicates in the cytoplasm.  Peptides derived from L. monocytogenes in the 
phagolysosome and the cytosol can be presented by both the MHC Class I and Class II molecules, 
inducing both CD4+ and CD8+ T-cell responses.  Listeria has other useful properties, such as stimulating 
monopoiesis, stimulating the differentiation and maturation of APC, and the generation of a particularly 
strong innate immune response.43   
 
Advaxis builds upon the unique attributes of Listeria by engineering a highly attenuated strain to release 
HPV-E7 antigen as a fusion protein to a non-hemolytic fragment of the Listeria protein Listeriolysin O 
(LLO) within the cytoplasm of the APC, resulting in more potent and broad CTL responses to the target 
antigen. The HPV tumor antigen proteins E6 and E7 are constitutively expressed in the nucleus of HPV 
associated tumors.  Most therapies targeting these antigens are directed at cellular immune responses.  
The ability to deliver antigen to the cytosolic compartment of APCs in order to develop HLA Class I 
presentation to induce CD8+ cytotoxic T cell responses appears to be an important aspect of developing 
an effective therapeutic anti-tumor vaccine. 
 
LLO is a virulence factor of Lm as it enables the bacterium to escape from the phagolysosome and thus 
become virulent.  As such, it appears to have evolved as a target of the immune system and stimulates 
many potentially therapeutic immune responses by itself, independent of the microbe.  By using it as part 
of a fusion protein along with an antigen this vaccine secretes a combined antigen-adjuvant directly 
within both the phagolysosome and cytoplasm of APC. 
 
There is evidence that Lm also gets into tumors, probably carried by infected macrophages and 
neutrophils.  Live Listeria vaccines that secrete an LLO-antigen fusion, but not those that secrete only an 
antigen, are able to diminish regulatory T cells within the tumor, but not in the spleen or normal 
peripheral tissues.44,45 
 
2.4  
Listeria monocytogenes Expressing HPV 16-E7 (ADXS11-001 Immunotherapy) 
 
ADXS11-001 is a live attenuated Listeria monocytogenes (Lm) 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. 
 
ADXS11-001 is manufactured for Advaxis, Inc. by Cobra Biomanufacturing PLC in the UK at EU and 
FDA certified facilities, and with open Drug Master Files in place on both continents.  Clinical materials 
have been manufactured under GMP conditions and in compliance with GMP regulations, and are so 
documented.46-59  Please refer to Advaxis Inc IND#13712. 


3/28/16/pg. 6 
 
 
2.5 
ADXS11-001 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. 
 
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 T-cells are generated where possible, 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. 
 
2.6  Non clinical Studies 
(The following studies are described in depth in the investigator brochure for ADXS11-001.) 
Advaxis chose the Balb/C strain of mice in order to test the toxicity of ADXS11-001 in the most stringent 
manner and to assess the worst case. Balb/C mice are deficient in their ability to kill or inhibit the growth 
of Lm organisms. Thus, the use of Balb/C mice provides the most stringent and rigorous assessment of the 
toxicologic properties of ADXS11-001 due to low level of cell mediated immunity response.  
 
2.6.1 Acute Single Dose Toxicity  
The purpose of this study was to assess the maximum tolerated dose (MTD) of ADXS11-001 
administered subcutaneously (SC) and intravenously (IV) to female Balb/C mice and to compare that 
tolerability to Wild Type Lm and Lm-SIV-Env (an early HIV construct that was found to be a more 
virulent Lm construct than ADXS11-001). A dose of 0.1 ml was administered on the day of dosing and all 
animals were observed once a day for seven days thereafter for mortality and signs of toxicity. Body 
weights were taken day of dosing and at day of termination. All surviving mice were sacrificed on Day 7 
and gross necropsies were performed with all lesions recorded. Based on data obtained during the in-life 
phase and gross pathology at necropsy, it was found that MTD for IV administered Lm-LLO-E7 to be 2.8 
x 107 and SC administered Lm-LLO-E7 to be 2.8 x 109. The IV administered Lm-LLO-E7 at 2.8 x 109 
resulted in a slight spleen enlargement in two mice, which while an acceptable adverse event in the 
treatment of cancer, prevented this dose from being classified as the MTD by definition. There were no 
clinical signs during the in-life phase or abnormalities at necropsy in the saline IV or SC groups of mice. 
The MTD for IV administered WT Lm was 103 and for the SC group the MTD was not observed as all 


3/28/16/pg. 7 
 
five mice in the 103 exhibited slight piloerection from day 2 to termination. At higher doses there were 
deaths, severe clinical signs of toxicity during in-life phase and pathology reported in the necropsies. The 
MTD for IV Lm-SIV-Env was 104 and no MTD was established for the SC dose group. In the higher dose 
groups for both IV and SC Lm-SIV-Env, there were clinical signs of toxicity during the in-life phase 
observations and gross pathology at necropsy. One mouse died on day 6 in the SC 108 treatment group.  
 
2.6.2 Multi-dose 28 day Toxicity Study  
Advaxis assessed the toxicity of ADXS11-001 when administered once weekly for four weeks either SC 
or IV to female Balb/C mice. On days 0, 7, 14, and 21, 0.1 ml of ADXS11-001 or saline control was 
administered to ten mice per group. All animals were observed twice daily for mortality and clinical signs 
of toxicity. Body weights were taken on days -1, 7, 14, and 28. Blood samples were taken on day 28 from 
five animals per group for serum chemistry and five animals for hematology. The shipment with 
hematology samples had delays in transit to the laboratory so there is no hematology data. All surviving 
mice were sacrificed on day 28 and gross necropsies were performed with all lesions recorded. A total of 
26 tissues were collected and sent to Biotechnics, Inc. for histopathologic analysis. This study 
demonstrated in-life phase observations for clinical signs of toxicity indicated weight loss that averaged 
1.2 grams in only one group IV 2.8 x 109. Two mice, one from IV 2.8 x 107 and one from IV 2.8 x 109, 
died immediately following the intravenous injection on Day 7 apparently unrelated to Lm. The attending 
veterinarian recorded the death as possibility being from volume shock. There were no other mortalities in 
the other groups or at later dates. General health observations for toxicity reported no observable 
abnormalities in the saline group, IV 105, IV 107, SC 105 and SC 107. All mice receiving IV 109 reported 
piloerection lasting for a couple days following injections on day 14 and 21. All animals in SC 109 
reported piloerection following injections on days 2-3, 14-17 and 23-28. Also, lumps developed at the SC 
dose sites on all group 7 mice on day 14-17 and 21-28. Overall, there was an increase in the liver enzymes 
(ALT, AST and ALP) in the ADXS11-001 treated mice over the saline controls and there was an increase 
in globulin levels in the SC and IV high dose groups. Necropsies reported gross pathological finding 
mostly in the SC and IV high dose groups and the most common finding was enlarged spleens and in the 
SC group lumps at the injection site. All histopathologic findings in the ten saline-treated mice were 
considered incidental. All IV 2.8 x 109 mice demonstrated histologic alterations within the liver and 
kidneys. The liver exhibited multifocal, random accumulations of mixed inflammatory cells including 
macrophages, lymphocytes, and neutrophils. Infiltration was minimal to occasionally mild but was 
typically disseminated, with numerous foci (>25 per section in 8 mice and <10 in one mouse) scattered 
throughout the hepatic parenchyma. Kidneys were variably affected and bore tubular alterations 
consisting of dilatation, epithelial attenuation, and regeneration. Active neutrophilic pyelonephritis was 
present in several mice. The numerous inflammatory foci disseminated throughout the liver and the 
tubular alterations in the kidney are indicative of an infectious state. The majority of IV 2.8 x 105 mice  
demonstrated histologic alterations within the liver. The liver exhibited multifocal, random accumulations 
of mixed inflammatory cells including macrophages, lymphocytes, and neutrophils. Infiltration was 
minimal, with approximately 5-20 cells per foci and <10 foci per section in 6 mice and 10-20 foci per 
section in 2 mice.  
 
2.6.3 Toxicity of Four Doses given One Month Apart with Ampicillin Treatment and Recovery 
Period 
Study 110607-07 was designed to evaluate the safety of 4 vaccinations of ADXS11-001 given at 1-month 
intervals in Balb/c mice. The study incorporated a prior treatment with cyclophosphamide one day before 
ADXS11-001 and oral ampicillin for 10 days starting 5 days after each vaccine dose in order to mimic the 
proposed patient populations and clinical regimen. Cyclophosphamide was given as an immuno-
conditioning agent to deplete aspects of the immune system (regulatory T cells).  
 
Fifty female mice were divided into two groups of 20 to receive 7.6 x 107 or 7.6 x 106 CFU ADXS11-001 
given IV and a Control group of 10 mice to receive saline. Cyclophosphamide at 30mg/kg was given IV 
to all animals on day 0. Groups were vaccinated on days 1, 31, 61, and 91. All mice received a 10-day 
course of oral ampicillin given by gavage at 50mg/kg/day starting on the fifth day after each vaccination. 


3/28/16/pg. 8 
 
Animals were observed for mortality and pharmacologic/toxicologic effects. Ten mice from each group 
were sacrificed for necropsy, histology, blood chemistry and hematology on day 111. Following an 
additional 21-day recovery period, the remaining (20) mice in the vaccinated groups were sacrificed on 
day 132.  Body weight gains were approximately the same in all groups. There were no observable 
abnormalities noted during post-dose observations on days of vaccination. In each group approximately 
10% of mice showed decreased activity, emaciation, piloerection, and/or hunched posture, but this were 
not considered to be related to test article (or placebo) administration. One animal died by drowning in 
Group 1 (day 25), due to malfunction of the watering device. One animal in Group 2 was found dead on 
day 28. Neither death was considered due to test article. There were no observable abnormalities at 
necropsy on either day 111 or day 132. The weight of lungs/trachea/pharnyx/larynx complex was 
significantly lower in the saline group. There were no significant differences in any other organ weights 
on day 111 or day 132. Serum chemistry results showed low albumin/globulin ratio for Group 1 high dose 
at day 111. Amylase was significantly high in this group at this time point. All other serum chemistry 
values were comparable to the saline group. At day 132, Group 1 high dose showed elevated ALT, AST 
and inorganic phosphorus; Group 2 low dose showed elevated AST.  On day 111, WCB counts were 
significantly lower in the high dose group. Day 132 results are not available due to poor blood sample 
quality.  Histopathology results showed mild inflammatory lesions in the livers of some mice, both test 
article-treated and saline groups. Most mice in all groups had moderate hemorrhagic lesions in the lungs. 
There were no histopathologically important 
 
2.6.4 Overall Conclusions from in vivo studies.  
No deaths attributable to ADXS11-001 were seen at any dose used in these studies. A total of three deaths 
in the 107 and 109 dosage groups were reported in one study, the 28 day toxicity study (42), and all deaths 
occurred within minutes of administration; a time course consistent with volume shock and not with 
infectious disease or the toxicity of ADXS11-001, which was the ascription made by the test laboratory. 
An equivalence calculation reveals that 0.1 ml in a mouse is the equivalent of 300 ml in a human, and the 
injection was administered over a 3-5 second interval. Thus, the potential for volume shock existed. No 
other deaths were observed in any study. 
 
The highest dose used in the panel of studies reported here was 2.8x109, which was used consistently in 
all studies, except in the SCID mouse trial. This dosage resulted in behavioral toxicity as evidenced by 
piloerection, modest weight loss, and histopathologic changes noted above. This dosage equates with a 
human dose of either 7.8x1012 if equated by mass, or 7.45x1011 if equated by surface area. Thus, in a 
species of mouse with a known deficit in its immunologic ability to respond to Lm infection, toxicity was 
only seen at doses that are significantly higher than those proposed in the initial clinical protocol.  
It should be noted to the clinical investigator that IV administration in these Lm susceptible mice differed 
from the experience of IP administration that was commonly used in research studies in more robust 
species of mice. This route of administration appeared to result in a longer subclinical infection in the 
absence of antibiotics, although it appears as though the microbe would clear to sterility given sufficient 
time. This is believed to result from the increased delivery of the construct via this route to all target 
tissues, including the liver, and spleen where Lm is known to preferentially colonize. Also, the immune 
environment of the peritoneal cavity is known to minimize the infectivity of the micro-organism when 
compared to IV administration. Ampicillin administration, as described above, completely eradicated the 
microbe in all tissues tested.  
 
The major conclusions that can be reached from this body of data include:  
 
A dose of 2.8x107 was determined as the maximally tolerated dose, which corresponds to a 
human dose of 7.84x1010 by weight or 7.45x109 by surface area. This range consistent with the 
clinical doses proposed for the initial clinical trial. However, in the context of cancer therapy a 
certain amount of toxicity is tolerated to obtain maximal efficacy. Thus, the proposed dosages for 
the human study are safe, and probably below the dose that will eventually be used to treat 
disease.  


3/28/16/pg. 9 
 
 
The persistence of the construct in the liver of animals not receiving antibiotic indicates that the 
clinician should assess hepatic toxicity routinely. This was already known as a site of Lm toxicity, 
and our work re-confirms this finding.  
 
Ampicillin, as well as 9 of the 11 tested antibiotics, is an effective antibiotic capable of 
eradicating the construct in the event of a toxic response.  
 
2.7 
Summary of previous clinical studies 
Refer to the Investigator Brochure (IB) for detailed preclinical and clinical data. 
 
2.7.1  Lm-LLO-E7-01:  Phase 1 Experience 
In the initial Phase 1 dose escalation study (Lm-LLO-E7-01), ADXS11-001 was assessed in 15 subjects 
with previously treated metastatic, refractory or recurrent invasive cervical cancer [60].  ADXS11-001 
was administered as an intravenous (IV) infusion at doses of 1 x 109 to 1 x 1010 CFU followed by a 
second dose 3 weeks later.  Overall, ADXS11-001 infusion was safely administered and well tolerated in 
end-stage subjects who had failed multiple prior therapies. 
 
No pre-medications were given in this study and all subjects experienced flu-like symptoms and/or 
symptoms associated with CRS.  The most commonly reported AEs were pyrexia (100%), vomiting 
(60%), chills, headache and anemia (53.3% each), nausea and tachycardia (46.7% each), and 
musculoskeletal pain (26.7%).  At all doses, AEs were acute and transient in most subjects, and responded 
to non-prescription symptomatic treatment with no observed listeriosis or Lm shedding.  A total of 9 
(60%) subjects experienced Grade 3 AEs, and in 6 (40%) of those subjects AEs were considered 
treatment-related (pyrexia in 3 subjects, fatigue in 1 subject, and increased gamma-glutamyltransferase 
[GGT] levels in 2 subjects).  No Grade 4 AEs were observed.  The highest dose of 1 x 1010 CFU led to a 
dose-limiting toxicity (DLT) of Grade 2 diastolic hypotension.  Under typical interpretation of a DLT (as 
defined per the protocol) in Phase 1 clinical studies in refractory cancers, this AE would not have met the 
criteria for DLT.  Two deaths occurred during the study period and were considered unrelated to 
ADXS11-001 administration.  Although not designed to assess efficacy, stable disease (SD) was reported 
in 7 of 13 (54%) evaluable subjects, and 1 subject (8%) had an unconfirmed partial tumor response.  
Based on the AE profile, all subsequent studies incorporate the administration of NSAIDs and antiemetic 
medications pre- and post-infusion to help reduce the incidence and severity of AEs related to cytokine 
release.  As an additional precaution, a course of oral antibiotics is initiated on Day 3 post-dosing of 
ADXS11-001 to assist in clearance of the Lm.   
 
2.7.2  Lm-LLO-E7-15:  Phase 2 Study of ADXS11-001 vs ADXS11-001 and Cisplatin in 
Recurrent, Refractory Cervical Cancer 
Lm-LLO-E7-15, was a randomized, multicenter, actively controlled Phase 2 study evaluating the safety 
and efficacy of ADXS11-001 alone compared with ADXS11 001 + cisplatin in 110 subjects with 
advanced cervical cancer that recurred after prior cytotoxic therapy, including chemotherapy and/or 
radiotherapy.  Eligible subjects were randomized 1:1 to ADXS11-001 or ADXS11-001 + cisplatin.  
Subjects in the ADXS11-001 group received 1 cycle (3 doses of 1 x 109 CFU) of ADXS11-001 at 28-day 
intervals.  Subjects in the ADXS11-001 + cisplatin group received a single dose of ADXS11-001, 
followed 28 days later by 5 weekly doses of cisplatin (40 mg/m2), followed 28 days later by 1 cycle of 
ADXS11-001; as a precautionary measure, a course of oral antibiotics was given to ensure clearance of 
the Lm .  After first dosing, subjects were followed at 3, 6, 9, 12, and 18 months; 109 subjects received 
264 doses of ADXS11-001. 
 
The primary endpoint of the study was OS.  Of 109 enrolled subjects, 89 (81.7%) subjects at 3 months, 70 
(64.2%) at 6 months, 49 (45%) at 9 months, 35 (32%) at 12 months, and 24 (22%) at 18 months were 
alive, suggesting that ADXS11-001 is an active agent in recurrent cervical cancer.  There was no 
statistically significant difference in the median duration of OS between ADXS11-001 and ADXS11-001 
+ cisplatin (p = 0.9993), nor was there any statistically significant effect of disease status, prior therapy, 


3/28/16/pg. 10 
 
or Eastern Cooperative Oncology Group (ECOG) performance status on OS between treatment groups. 
 
Of 69 subjects in the efficacy population, 10% of subjects had an objective tumor response.  Complete 
response (CR) was recorded as the best response in 5 subjects (3 ADXS11-001; 2 ADXS11-001 + 
cisplatin), partial response (PR) in 6 subjects (3 ADXS11-001; 3 ADXS11-001 + cisplatin), SD in 31 
subjects (16 ADXS11-001; 15 ADXS11-001 + cisplatin), and progressive disease (PD) in 27 subjects (13 
ADXS11-001; 14 ADXS11-001 + cisplatin).  Tumor response at 3, 6, 9, 12, and 18 months was 
comparable between treatment groups.  The disease control rate was 39% (42/109).  Results of the safety 
profile are shown in Table 1.  
 
2.7.3 
GOG-0265:  Phase 2 Evaluation of ADXS11-01 in Recurrent, Refractory Cervical Cancer 
GOG 0265 is an ongoing study being conducted by the GOG, through sponsorship by the NCI Cancer 
Therapy Evaluation Program (CTEP).  It is a 2-stage study designed to evaluate ADXS11-001 (3 doses of 
1 x 109 administered every 4 weeks) in subjects with advanced, metastatic, or recurrent squamous or non-
squamous carcinoma of the cervix who have had at least 1 prior systemic chemotherapeutic regimen in 
the metastatic setting.  The primary objectives of the study are to evaluate: 
 
1. The tolerability, safety, nature and degree of toxicity of ADXS11-001 by the numbers of subjects 
with DLTs and AEs as assessed by CTCAE v 4.03 
2. To assess the activity of ADXS11-001 for subjects with persistent or recurrent carcinoma of the 
cervix by the frequency of subjects who survive for at least 12 months after initiating therapy 
 
Twenty-nine subjects were enrolled to Stage 1 of the study, of which 3 were never treated with ADXS11-
001.  Among the 26 subjects, 8 (30%) had 1 prior therapy, 14 (54%) had 2 prior therapies and 4 (16%) 
had 3 prior therapies for treatment of their metastatic disease.  The study is being conducted according to 
the GOG’s standard Simon 2-stage design (for recurrent/refractory cervical cancer).  A Stage 1 efficacy 
bar of 20% 12-month survival was established as a predetermined criterion (by a logistic regression 
model from 17 studies conducted by GOG in over 500 subjects with recurrent/refractory cervical cancer) 
to be met in order for the study to proceed to Stage 2. Based on the historical data in subjects with 
recurrent/refractory cervical cancer, the expected 12-month survival rate is 10-15%. 
 
As of May 2015, Stage 1 of GOG-0265 is complete with 26 subjects receiving at least 1 dose of 
ADXS11-001.  The 12 month survival rate from Stage 1 was 38% (10/26) with a 7.7 month median 
survival.  Stage 2 of the study opened on March 11, 2015 and will enroll approximately 37 subjects.  The 
study has been amended to allow for treatment with ADXS11-001 until disease progression as per 
RECIST 1.1, and to limit the number of prior therapies in the metastatic setting to no more than 1 prior 
therapy. 
 
2.7.4 Updated previous clinical experience: 
As of January 1, 2015, 573 doses of ADXS11-001 have been administered to 229/230 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 230 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.  There have been no persistent symptoms or cumulative toxicity observed in subsequent doses.  
Although subjects have manifested cytokine release symptoms, no single subject has manifested all of the 


3/28/16/pg. 11 
 
following symptoms collectively: nausea, headache, tachycardia, hypotension, rash, and shortness of 
breath per NCI CTCAE v 4.03 that defines cytokine release syndrome (CRS).  
A summary of AEs in >5% of patients by MedDRA system organ class and preferred term is presented in 
Table 1.  There have been no Grade 3-4 drug related AEs observed in over 5% of the patient population 
(see Table 2). 
Table 1  Number (%) of Subjects with Adverse Events >5% Incidence (Safety Population, N=230) 
System Organ Class (SOC),n % [1] 
Grades 1-4 
(N=230) 
Grade 3-4 
(N=230) 
Blood And Lymphatic System Disorders 
 
 
 
Anaemia 
80 (34.8 %) 
35 (15.2 %) 
Cardiac Disorders 
 
 
 
Tachycardia 
13 (5.7 %) 
- 
Gastrointestinal Disorders 
 
 
 
Abdominal Pain 
34 (14.8 %) 
4 (1.7 %) 
 
Constipation 
29 (12.6 %) 
1 (0.4 %) 
 
Diarrhoea 
16 (7.0 %) 
3 (1.3 %) 
 
Nausea 
64 (27.8 %) 
2 (0.9 %) 
 
Vomiting 
46 (20.0 %) 
4 (1.7 %) 
General Disorders And Administration Site Conditions 
 
 
 
Chills 
89 (38.7 %) 
2 (0.9 %) 
 
Disease Progression 
- 
- 
 
Fatigue 
41 (17.8 %) 
2 (0.9 %) 
 
Oedema Peripheral 
14 (6.1 %) 
- 
 
Pain 
19 (8.3 %) 
3 (1.3 %) 
 
Pyrexia 
71 (30.9 %) 
3 (1.3 %) 
Investigations 
 
 
 
Alanine Aminotransferase Increased 
12 (5.2 %) 
2 (0.9 %) 
 
Aspartate Aminotransferase Increased 
14 (6.1 %) 
2 (0.9 %) 
 
Blood Alkaline Phosphatase Increased 
15 (6.5 %) 
2 (0.9 %) 
 
Blood Creatinine Increased 
16 (7.0 %) 
6 (2.6 %) 
 
Gamma-Glutamyltransferase Increased 
14 (6.1 %) 
3 (1.3 %) 
 
Haemoglobin Decreased 
12 (5.2 %) 
2 (0.9 %) 
 
White Blood Cell Count Decreased 
20 (8.7 %) 
7 (3.0 %) 
Metabolism And Nutrition Disorders 
 
 
 
Decreased Appetite 
21 (9.1 %) 
- 


3/28/16/pg. 12 
 
System Organ Class (SOC),n % [1] 
Grades 1-4 
(N=230) 
Grade 3-4 
(N=230) 
 
Hypoalbuminaemia 
28 (12.2 %) 
9 (3.9 %) 
 
Hypocalcaemia 
13 (5.7 %) 
2 (0.9 %) 
 
Hypokalaemia 
15 (6.5 %) 
4 (1.7 %) 
 
Hyponatraemia 
19 (8.3 %) 
9 (3.9 %) 
Musculoskeletal And Connective Tissue Disorders 
 
 
 
Back Pain 
17 (7.4 %) 
3 (1.3 %) 
Nervous System Disorders 
 
 
 
Dizziness 
12 (5.2 %) 
- 
 
Headache 
41 (17.8 %) 
- 
Respiratory, Thoracic And Mediastinal Disorders 
 
 
 
Dyspnoea 
14 (6.1 %) 
1 (0.4 %) 
Vascular Disorders 
 
 
 
Hypotension 
16 (7.0 %) 
2 (0.9 %) 
Note:  [1] Percentage is calculated using column header count as denominator for percentage calculation. 
 
Table 2  Number (%) of Subjects with Adverse Events >5% with Respect to Relationship (Possibly 
Related, Probably Related and Related) (Safety Population, N=230) 
System Organ Class (SOC),n % [1] 
Grades 1-4 
(N=230) 
Grade 3-4 
(N=230) 
Blood And Lymphatic System Disorders 
 
 
 
Anaemia 
18 (7.8 %) 
2 (0.9 %) 
Gastrointestinal Disorders 
 
 
 
Nausea 
47 (20.4 %) 
- 
 
Vomiting 
31 (13.5 %) 
2 (0.9 %) 
General Disorders And Administration Site Conditions 
 
 
 
Chills 
78 (33.9 %) 
2 (0.9 %) 
 
Fatigue 
27 (11.7 %) 
1 (0.4 %) 
 
Pyrexia 
57 (24.8 %) 
3 (1.3 %) 
Nervous System Disorders 
 
 
 
Headache 
36 (15.7 %) 
- 
Vascular Disorders 
 
 
 
Hypotension 
15 (6.5 %) 
2 (0.9 %) 


3/28/16/pg. 13 
 
System Organ Class (SOC),n % [1] 
Grades 1-4 
(N=230) 
Grade 3-4 
(N=230) 
Note:  [1] Percentage is calculated using column header count as denominator for percentage calculation. 
 
 
2.7.5 Delayed/Late Listeria Infection: 
ADXS11-001 has been attenuated over 4 logs more in comparison to the wild-type (wt)-Lm.  ADXS11-
001 is cleared by SCID mice lacking a functioning cellular immune system and 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 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) [60].  
wt-Lm is known to form and persist within biofilms especially on medical devices despite antibiotic 
treatment [69]. Although rare, medical device–related infections such as ventriculo-peritoneal shunt 
infection, peritoneovenous shunt infection, and prosthetic joint infection have been reported [70-73]. 
ADXS11-001is highly sensitive to antibiotics such as ampicillin and sulfamethoxazole/trimethoprim 
which can be an effective treatment regimen for listeria infection. Therefore, subjects with implanted 
medical device(s) that pose a high risk for colonization and/or cannot be easily removed are excluded 
from this study. In addition, all subjects will receive a course of oral antibiotics beginning on Day 4 
(approximately 72 hours) after each dose of ADXS11-001 and for 6 months following the last dose of 
ADXS11-001 to aid in the eradication of the bacteria.   
As of September 2015, approximately 263 subjects have received approximately 675 doses of ADXS11-
001. During the course of treatment in subjects with various cancers, there has been one reported case of 
Grade 3 listeriosis (0.38%). The subject was a 56 year old female who was enrolled in 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 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 patient refused. Two weeks later, 
the subject presented with acute respiratory distress caused by her metastatic disease and died. The 
investigator ruled the cause of death was due to disease progression (metastatic cervical cancer).  It is 
hypothesized that dosing of attenuated Lm soon after her bone graft likely resulted in biofilm formation, 
which protected the organisms 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. 
Genomic sequencing confirmed by PCR later revealed that the Lm was avirulent, and therefore incapable 
of spreading cell-to-cell. The Lm isolate also remained highly susceptible to multiple antibiotics.   
 
 
 


3/28/16/pg. 14 
 
2.8 Six-Month Clinical Complete Response As Efficacy Endpoint In Anal Cancer After 
Chemoradiation: 
The optimal time for performing a post treatment proctoscopy and biopsy in anal cancer is controversial. 
Results from the ACT II trial, a 940 patient anal cancer clinical trial, demonstrated that clinical complete 
response at 6 months is predictive of progression free survival.62 Therefore an efficacy endpoint for this 
trial will be the rate of clinical complete response as determined by evaluation by proctoscopy at 6 
months.  
 
2.9 Protocol Rationale: 
Novel treatments are needed in anal cancer. An important percentage of patients with locally advanced 
anal cancer will have persistent loco-regional disease or develop systemic metastases. Virtually all cases 
of anal cancer are related to infection by HPV. Anal cancer cells infected with HPV have the tumor 
associated antigen HPV E7. ADXS11-001 causes antigen presenting cells to be stimulated to facilitate 
immune cells to attack cancer cells expressing HPV E7. ADXS11-001, at the phase II dose of 1x109 CFU, 
has been shown to be safe in patients with advanced cervical cancer which also is caused by HPV 
infection. Anti-tumor activity and safety have been demonstrated in cervical cancer to single agent 
ADXS11-001 and the combination of ADXS11-001 and cisplatin chemotherapy. Data presented at ASCO 
2012 ADXS11-001 is currently being evaluated in women in the United States with cervical 
intraepithelial neoplasia. Radiation may augment the activity of ADXS11-001 increasing the exposure of 
tumor related antigens thereby increasing the chance for loco-regional disease eradication and preventing 
systemic recurrence. Therefore, ADXS11-001 may increase complete response, prevent recurrence 
disease and increase disease-free and overall survival in anal cancer. This protocol will develop sufficient 
preliminary safety and efficacy data to facilitate the investigation of ADXS11-001 in anal cancer within 
“NRG”, the newly formed cooperative group based on the merger of the RTOG, NSABP and GOG. 
 
As described above, Phase I studies and preliminary data from phase II studies have demonstrated that 
ADXS11-001, 1x109 CFU, can be safely administered as a single agent and in combination with 
chemotherapy. For example in over 200 patients treated at the dose of 1x109CFU there have been no 
cases of severe listeria bacteremia or grade 3 cardiopulmonary toxicity. However, since ADXS11-001 has 
not previously been administered with radiation, we will confirm safety and investigate effectiveness with 
the primary objective of this study being to establish the safety of the addition of ADXS11-001 to 
chemoradiation for anal cancer.  
  
 
Treatment Schedule: The first dose will be given 6-14 days prior to the initiation of 
chemoradiation. The 2nd-4th dosages of ADXS11-001will not be until after completion of all 
chemoradiation. The second dosage of ADXS11-001 will not be administered until a minimum of 
10 days (10- 28 days) after completion of chemoradiation, ANC > 1,000 cells/mm3, serum 
creatinine < 1.5 mg/dl and all toxicities from chemoradiation have resolved to grade 2 or less. *If 
in the investigators opinion a delay for vaccine # 2 is necessary post chemo/RT it is allowable for 
vaccine # 2 to be given with a + 2 week window but reason and delay must be documented and 
submitted to BrUOG.* The subsequent third and fourth treatment with of ADXS11-001 will be 
administered at 28 day intervals (+7 days). Standard treatment with mitomycin, 5-FU and 
radiation for anal cancer has substantial toxicity. In RTOG 9811, 74% of patients had grade 3/4 
nonhematologic toxicity and 61% of patients had grade 3 or grade 4 hematologic toxicity from 
this regimen. Therefore, the toxicities of standard chemoradiation with mitomycin, 5-FU and 
radiation are well above the conventionally accepted parameters in a phase I study even prior to 
adding ADXS11-001. However, it is critical that the addition of ADXS11-001 does not 
compromise the delivery of potentially curative standard chemoradiation for anal cancer.  
 
Therefore we define toxicities for patient removal as:  
 
Grade 4 treatment related toxicities lasting greater than 7 days 
 
Febrile neutropenia lasting > 7 days. 


3/28/16/pg. 15 
 
 
Inability to administer full dose of intended radiation within a period of 14 weeks due to 
treatment related toxicities. 
 
Persistence of listeria bacteremia as documented by positive blood cultures for > 3 days (> 72 
hours). 
 
Documented bacterial meningitis 
 
Clinical sepsis requiring pressors. 
 
2.10 Protocol Coordination: 
The protocol will be centrally coordinated by the Brown University Oncology research Group. The 
principal investigator, Dr. Howard Safran, will hold the IND. The primary contract for the clinical 
management of the study will be between Advaxis and Rhode Island Hospital, the principal teaching 
hospital of the Brown University Oncology research Group. Rhode Island Hospital will coordinate 
subcontracts with all other participating institutions. The Brown University Oncology research Group 
central office will be responsible for clinical, data and regulatory oversight of all participating sites. (See 
section 15.4.1 for more information on protocol coordination.) 
 
2.11 Phase I Data and Initiation of Phase II Component of Study: 
The Brown University Oncology Research Group initiated this phase I study with the goal of evaluating 
two different treatment schedules of ADXS11-001 with standard mitomycin, 5-FU and concurrent 
radiation. Patients with newly diagnosed anal cancer with a primary tumor > 4cm or lymph node 
involvement, without distant metastases were eligible. Patients received 2 courses of mitomycin, 5-FU 
with concurrent radiation (54 Gy in 30 fractions by IMRT). Patients were to receive 4 treatments of 
ADXS11-001, 1x109 colony forming units intravenously once approximately every 28 days. In treatment 
schedule #1, the first dose was given before chemoradiation and the 2-4th doses were given every 28 days 
after completion of radiation. In treatment schedule #2, the second dose of ADXS11-001 was to be 
administered currently during chemoradiation on day 21 (the week prior to the second course of 
chemoradiation.  
The goal of the Brown University Oncology Research Group study was to establish the safety of each 
treatment cycle to acquire the necessary preliminary data to evaluate ADXS11-001 with chemoradiation 
in the cooperative groups. Four patients have been treated with ADXS11-001 and chemoradiation on 
treatment schedule #1. The median age was 57. Two patients had N3 disease, one patient had N2 disease, 
and one patient had a T4 tumor with a fistula requiring a diverting colostomy prior to starting treatment.  
There has been no evidence of enhanced hematologic or non-hematologic toxicity from the addition of 
ADXS11-001. One patient developed grade 3 neutropenia. There have been no DLTs observed, and, as 
originally defined by the protocol, it has been determined that Treatment Schedule #1 is safe. However, of 
the four patients treated on Treatment Schedule #1, three had significant symptoms following infusion of 
ADXS11-001 including temporary rigors requiring 2-3 courses of IV meperidine. Patients also 
experienced fever and myalgia (lasting approximately 24 hours). One of these patients required overnight 
admission. These were expected toxicities and not of severity to characterize as dose limiting toxicities. 
However, the Brown University Oncology Research Group has decided not to evaluate Treatment 
Schedule #2. The intensity of the symptoms following infusion, are not unexpected in patients with a 
good performance status without exposure to prior chemotherapy, who are exposed to Listeria. These 
symptoms may be difficult to manage in a cooperative group setting on Treatment Schedule #2, when the 
ADXS11-001 infusion is given during chemoradiation, just prior to the second cycle of mitomycin and 5-
FU.  Fever and rigors produced by administration of day 21 ADXS11-001 could be quite problematic. 
Therefore, this amendment modifies the current clinical study to become a phase II trial to further 
evaluate treatment schedule #1. There will only be one treatment schedule assessed. 
 


3/28/16/pg. 16 
 
 
3.0 PATIENT ELIGIBILITY 
3.1 
Conditions for Patient Eligibility  
3.1.1 
Histologically-proven, invasive primary squamous, basaloid, or cloacogenic carcinoma of the 
anal canal; 
3.1.2       AJCC 2009 TN Stage: T1N1-N3, T2(< 4cm)N1-N3, T2(> 4cm)N0,T3N0-3, T4N0-3;based upon 
the following minimum diagnostic workup: 
3.1.2.1 History/physical examination within 14 days prior to registration; 
3.1.2.2 Within 42 days prior to registration, the patient must have an anal examination with 
documentation of primary anal lesion size and distance from the anal verge. The preference is by any of 
the following: colonoscopy, sigmoidoscopy, or rigid proctoscopy, however if patient underwent anoscope 
this can be used for documentation. If patient is unable to tolerate any scope, reason must be documented 
and MRI can be used for disease measurements, distance and monitoring of disease response. 
Documentation of primary anal lesion size and distance from the anal verge to be sent regardless of type 
of scope or imaging. 
3.1.3 Groin examination (clinical) within 42 days prior to registration with documentation of any groin 
adenopathy and lymphadenopathy (location: right vs. left; medial vs. lateral; mobile vs. fixed; and size); 
3.1.4 
X-ray (PA and lateral), CT scan, or PET/CT scan of the chest within 42 days prior to registration; 
3.1.5 
CT scan, MRI, or PET/CT of the abdomen and pelvis within 42 days prior to registration;  
3.1.6 
Zubrod Performance Status 0-1; 
3.1.7 
Age ≥ 18; 
3.1.8 
Laboratory data obtained ≤ 14 days prior to registration on study, with adequate bone marrow, 
hepatic and renal function defined as follows: 
 
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;  
 
Platelets ≥ 100,000 cells/mm3;  
 
Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 
g/dl is acceptable.); 
 
Serum creatinine ≤ 1.5 mg/dl; 
 
Bilirubin < 1.4mg/dl; 
 
ALT/AST < 3 x ULN; 
 
Negative serum pregnancy test for women of child-bearing potential; 
3.1.9 
Women of childbearing potential and male participants must agree to use a 2 forms of medically 
effective means of birth control (such as a condom and spermicide) throughout their participation in the 
treatment phase of the study and for 90 days post last dose of study drug. To be documented. 
3.1.10 Patients must sign a study-specific informed consent prior to study entry. 
3.1.11   Patients with a history of clinically significant pulmonary disease must have PFTs demonstrating 
a DLCO ≥ 40%. This testing is considered standard of care prior to mitomycin, 5-FU and radiation. 
3.1.12   Patients with a history of clinically significant cardiac disease must have a LVEF ≥ 30% by 
ECHO. (MUGA scan may also be used to determine LVEF) This testing is considered standard of care 
prior to mitomycin, 5-FU and radiation.  
3.1.13   Patients must be able to swallow pills. 
 
 
3.2 
Conditions for Patient Ineligibility  
3.2.1 
Prior invasive malignancy (except non-melanomatous skin cancer), unless disease free for a 
minimum of 2 years; 
3.2.2 
Prior systemic chemotherapy for anal cancer;  
3.2.3 
Prior allergic reaction to the study drugs involved in this protocol. 
3.2.4 
Prior radiotherapy to the pelvis that would result in overlap of radiation therapy fields; 
3.2.5 
Severe, active co-morbidity, defined as follows: 
 
3.2.5.1 Patients with uncontrolled intercurrent illness including, but not limited to ongoing or 
active infection, symptomatic congestive heart failure, unstable angina pectoris and cardiac 


3/28/16/pg. 17 
 
arrhythmia are ineligible. Furthermore, patients with unstable angina and/or congestive heart 
failure requiring hospitalization within the past 6 months are ineligible;  
 
Patients with active infection requiring systemic therapy (oral or IV) or those currently receiving 
antibiotics that cannot discontinue prior to dosing are ineligible. (Subjects who discontinue an 
antibiotic prior to dosing must wait at least 5 half-lives after the last dose of antibiotic before 
receiving any ADXS11-001 infusion- documentation required to be sent to BrUOG to confirm 
eligibility) 
 
3.2.5.2 Transmural myocardial infarction within the last 6 months; 
 
3.2.5.3 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration; 
 
3.2.5.4 Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy at the time of registration; 
 
3.2.5.5 Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; 
3.2.6 Patients known to be seropositive for HIV and/or active hepatitis, even if liver function studies are 
in the eligible range. 
 
3.2.7 
Other immunocompromised status (e.g., organ transplant or chronic glucocorticoid use). If patient 
has diagnosis of immunodeficiency, is dependent on or has received systemic steroids therapy or any 
form of immunosuppressive therapy within 7 days prior to the first dose of ADXS11-001 they are 
ineligible. Topical corticosteroid or occasional inhaled corticosteroids are allowed. 
3.2.8 
Women who are pregnant or lactating are ineligible because the treatment involved in this study 
may be significantly teratogenic and there is the potential for transmission of listeria to the infant. 
3.2.9 Patients allergic to or with sensitivity to penicillin, ampicillin, trimethoprim-sulfa and quinolones 
(including history of rash or anaphylaxis).  
3.2.10 Patients allergic to naproxen. 
3.2.11 Patients receiving oral or IV antibiotics 
3.2.12 Patients with a prior history of a splenectomy and/or sickle cell trait/disease 
3.2.13 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.  Sponsor must be contacted prior to consenting any subject who has 
any other device and/or implant. Site is required to submit to BrUOG ALL surgical implants patient has 
ever had in their medical history and ALL surgeries regardless of link to this cancer diagnosis.  
3.2.14 Patients who are receiving or may receive future treatment with PI3K or TNFα inhibitors. To be 
confirmed by treating medical oncologist in writing 
3.2.15 Has 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: if patient underwent surgery > 6 
weeks from start of ADSX11-001, all toxicities and/or complications must have recovered to baseline or 
Grade 1 prior to the initiation of ADXS11-001 study therapy and this must be documented for 
confirmation to BrUOG prior to registration.   
3.2.16 Patient not being willing to have new infusion line placed for each infusion of ADXS11-001 as 
existing or newly placed central venous catheter or infusion ports are not allowed to be used for 
ADXS11-001 administration. Must be confirmed as discussed with patient and that they agreed. 
3.2.17 Patient not willing to comply with requirement of central venous catheter or infusion port must 
not be used for 72 hours following the completion of the ADXS11-001 infusion and the patient receives 
the first post-treatment dose of oral antibiotics. Must be confirmed as discussed with patient and that they 
agreed. 
3.2.18 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., 


3/28/16/pg. 18 
 
Flu-Mist®) are live attenuated vaccines and are not allowed. All recent vaccines (within 30 days) to be 
listed on conmed log and submitted to BrUOG. 
3.2.19 Patient has a history of listeriosis or prior ADXS11-001 therapy. 
 
 
4.0 TREATMENT 
Treatment Schedule  
 
 
 
 
 
 
 
 
 
                                                                                                                                                                                         
BX Diagnosis                                                                                                                            
 
        BX 6 months 
Treatment Schedule:  The first dose will be given 6-14 days prior to the initiation of chemoradiation. The 
2-4th dosages of ADXS11-001 will not be until after completion of all chemoradiation. The second dosage 
of ADXS11-001 will not be administered until a minimum of 10 days (10-28 days) after completion of 
chemoradiation, ANC > 1,000 cells/mm3, Platelets ≥ 50,000 cells/mm3, serum creatinine < 1.5 mg/dl and 
all non-hematologic toxicities from chemoradiation have resolved to grade 2 or less. *If in the 
investigators opinion a delay for vaccine # 2 is necessary post chemo/RT it is allowable for vaccine # 2 to 
be given with a + 2 week window but reason and delay must be documented and submitted to BrUOG.* 
The subsequent third and fourth treatment of ADXS11-001 will be administered at 28 day intervals (+7 
days). The second cycle of chemotherapy may be +7 days. 
 
The biopsy post chemoradiation will be performed at approximately 6 months after day #1 of the 
initiation of chemoradiation if there is residual suspicious tissue seen on examination. 
 
In addition, all subjects enrolled with amendment # 16 will participate in a 3 year Lm surveillance 
period. 
 
Patients experiencing any the following toxicities will be removed from the study and should not 
receive any additional ADXS11-001 unless review of a specific case with clinical rationale provides 
support for patient to remain on study (information must be submitted to BrUOG with enough 
time for extensive review of the case): 
 
Grade 4 treatment related toxicities lasting greater than 3 weeks 
 
Febrile neutropenia lasting > 7 days. 
 
Inability to administer full dose of intended radiation within a period of 14 weeks due to 
treatment related toxicities.  
 
Persistence of listeria bacteremia as documented by positive blood cultures for > 3 days (> 72 
hours).  
 
Document bacterial meningitis 
 
Clinical sepsis requiring pressors. 
 
 
 
 
 
 
 
Mito/5-FU 
Day 29-32 
+ 7 days  
Mito/5-FU 
Day 1-4 
Radiation for 6 weeks 
ADX #1  
6-14 days 
pre-RT 
ADX 
#2 
 
ADX 
#3 
 
ADX 
#4 
 


3/28/16/pg. 19 
 
Major and Minor Surgeries and ADXS11-001 Treatment 
No formal studies of the effect of ADXS11-001 on wound healing have been conducted.  However, based 
on its mechanism of action it is not expected that administration of ADXS11-001 would complicate 
wound healing.  Therefore, a subject may initiate or resume study treatment 2 weeks after minor surgery 
(i.e. surgery involving little risk to the life of the patient; specifically an operation on the superficial 
structures of the body or a manipulative procedure that does not involve a serious risk) if the wound has 
completely healed and there are no wound healing complications.  A subject who has wound healing 
complications following minor surgery, received major surgery or requires 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. BrUOG consultation is required prior to resuming study treatment for these 
subjects.  If the treatment is delayed due to concomitant surgery beyond 12 weeks the subject may be 
discontinued from the study.  
On study, surgeries and/or procedures must be scheduled following the completion of 7 day course of 
prophylactic antibiotics post ADXS11-001 infusion.  In addition, “recommended antibiotic prophylaxis” 
per institution standards for respective surgeries/and or procedures must be followed. 
*BrUOG must be made aware of any surgery prior to it happening for review and please see section 11.1 
for SAE definitions and contact BrUOG to confirm if surgery needs to be reported as a SAE* 
 
 
4.1      ADX 
ADXS11-001 will be given at a dose of 1x109 cfu intravenously as per the treatment schedules described 
in Section 4.0.  All doses of ADXS11-001 will be 1x109 cfu. The drug will be given as a 250ml infusion 
over 60 minutes.  
 
ADXS11-001 must be administered 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.  
 
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. 
 
 
The following criteria must be met to receive ADXS11-001: 
 
ANC > 1,000 cells/mm3,  
 
Platelets ≥ 50,000 cells/mm3,   
 
Serum creatinine < 1.5 mg/dl  
 
All non-hematologic treatment related toxicities from chemoradiation have resolved to grade 2 or 
less. 
PRETREATMENT PROPHYLACTIC REGIMEN: 
 
Mild to moderate flu-like symptoms and 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 seen and typically occur 2-4 hours after 
ADXS11-001 infusion and often resolve within 12-24 hours.  Prophylactic medications are 


3/28/16/pg. 20 
 
intended to reduce the inflammatory response.  Subjects should receive the following 
pretreatment prophylaxis regimen:  
 
 
IV Fluid Hydration: 
 
Normal saline (e.g. 500 mL over 30 minutes) 
 
Premedication Regimen: 
 
 
Antihistamine- PO or IV (e.g., diphenhydramine 25mg or equivalent), once   
 
Naproxen, per schedule in section 4.1.2 
 
Antiemetic- PO or IV (e.g., promethazine or ondansetron ), once 
 
Histamine H2-receptor antagonist- PO or IV (e.g., famotidine 20 mg or equivalent), once 
Pretreatment medication should be given on the day of dosing and completed approximately 30 minutes 
prior to the start of the assigned study treatment infusion.  Additional NSAID doses and antiemetic 
administration should be given per label or package insert post initial administration on Day 1 and Day 2, 
as needed.  The prescribed dosage of the selected NSAID and antiemetic will be at the discretion of the 
Investigator. 
Do not substitute acetaminophen for the selected NSAID for prophylactic treatment since acetaminophen 
does not have similar anti-inflammatory properties that could ameliorate cytokine release symptoms. 
 
4.1.1 Antibiotics: At approximately 72 hours following each dose a 7 day regimen of oral antibiotics will 
be administered.  Subjects will receive a 7 day course of either oral 80mg trimethoprim / 400 mg 
sulfamethoxazole once daily (x 7 days) or double strength, 160 mg trimethoprim / 800 mg 
sulfamethoxazole (DS) three times over the course of the 7 days. Subjects with known allergy to sulfa 
drugs may receive ampicillin 500 mg four times daily for 7 days beginning on Day 4 (approximately 72 
hours) after each ADXS11-001 infusion.  If calculated creatinine clearance is 10-50 mL/min, change 
frequency of oral ampicillin to TID. If calculated creatinine clearance is <10 mL/min, change frequency 
of oral ampicillin to BID.  
 
Post Study Treatment - All subjects who enroll to this study with or after amendment # 16, will receive a 
6 month course of oral trimethoprim/sulfamethoxazole or ampicillin for subjects with sulfa allergies to be 
initiated approximately 72 hours following the last dose of study treatment or at the time of study 
discontinuation. Trimethoprim/sulfamethoxazole therapy should consist of either 160 mg 
trimethoprim/800 mg sulfamethoxazole (DS) tablet administered three times a week or 80 mg 
trimethoprim/400 mg sulfamethoxazole administered daily for 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. 
 
4.1.2 Naproxen: Patients will take naproxen beginning the day prior to each ADXS11-001 treatment.  
The dose of naproxen will be 440mg x 1 (first dose), followed by 220mg every 12 hours.  The patient will 
receive a minimum of 4 doses of naproxen with each cycle (the day prior to dosing:  440mg in the 
morning and 220mg in the evening; Day 1:  220mg in the morning and 220mg in the evening).  On the 
day of dosing with ADXS11-001, patients will take the AM dose of naproxen prior to arrival to the study 
site.  Do not substitute acetaminophen or other NSAID for naproxen. 
 
4.1.3: Antiemetics:  
On the day of receiving ADXS11-001, patients will receive an oral or intravenous 
antiemetic/anticholinergic, such as promethazine (Phenergan), prochlorperazine or ondansetron .  If an 
oral regimen such as promethazine is chosen, two doses of oral promethazine (25 mg) are to be 


3/28/16/pg. 21 
 
administered.  One dose will begin just prior to the onset of the infusion at approximately 7:30 am, and a 
second dose will be given to the patient to take 8-12 hours after the first dose to mitigate possible side 
effects.  An alternative antiemetic can be substituted at the discretion of the treating physician.  On the 
date of receiving ADXS11-001, patients will also receive naproxen (as noted in section 4.1.2), an 
antihistamine , oral or IV, once, and a histamine H2-receptor antagonist, oral or IV, once. Pretreatment 
medication should be given on the day of dosing and completed approximately 30 minutes prior to the 
start of the assigned study treatment infusion.   
 
Patients should be advised to continue naproxen prn (per the OTC label instructions) following each dose 
of ADXS11-001 dose until any symptoms subside.   
 
4.1.4 Patient Monitoring and Assessment with ADXS11-001:  
Treatment is to be done on an outpatient basis.  Patients will be observed in the outpatient area for 4 hours 
following the ADXS11-001 infusion.  Vital signs will be taken pre-dose, 30 minutes,1 hour, 90 minutes, 2 
hours, 2.5 hours, 3 hours, 3.5 hours and 4 hours after dose (+/- 15 minutes given for all time points except 
4 hours post which is only +15 minutes).  Patients will return on Day 2 for toxicity assessment and vital 
signs 24 hours (+/- 2 hours) after dose.  Patients will return 72 hours after dosing for toxicity assessment 
and vital signs. 
 
Day 1 of each treatment:  At 4 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.  If a patient’s baseline (medical history) HR, blood pressure, 
respiration are not within normal limits but are within their normal medical history limits, documentation 
is to be made to note baseline medical history values and treating investigator to document that vital signs 
are not clinically significant or related and rather per patient’s medical history.  
A subject who experiences a fever (CTCAE Grade 1 or greater) 24 hours following the completion of 
ADXS11-001 infusion should be started on NSAIDS, hydration and other appropriate measures to treat 
the fever. In the event that the fever persists or worsens 48 hours following the completion of ADXS11-
001 infusion then oral or broad spectrum IV antibiotics should be considered based on the subject’s 
medical condition. If the fever remains unresponsive to oral/IV antibiotics 72 hours following the 
completion of the infusion then a blood culture should be obtained to evaluate for listeremia and 
determine the appropriate treatment course for the subject.  
In the event a patient experiences a persistent fever at 72 hours after receiving ADXS11-001 the oral 
regimen below will be preceded by an IV dose of 500 mg of ampicillin.  If calculated creatinine clearance 
is <10 mL/min, change dose of IV ampicillin to 250mg. 
Patients should be monitored carefully for symptoms of bacterial meningitis, i.e., fever, stiff neck, 
headaches and altered mental status.  Neurology and Infectious Disease consultation should be obtained if 
appropriate.  All patients when stable for discharge should complete a regimen of antibiotics (beginning 
on 72 hours after administration of study drug, if not already started) for 7days to ensure resolution of the 
infection. 
 
Hypotension grade 1 will be defined, using CTCAE criteria, as a blood pressure (BP) for which 
intervention is not needed and where the patient is asymptomatic. At the baseline/registration 
appointment, the patient’s BP is to be assessed based on their medical history and normal value. Per 
CTCAE hypotension is defined as: a disorder characterized by a blood pressure that is below the normal 
expected for an individual in a given environment. For all changes (drops) in blood pressure, for which 


3/28/16/pg. 22 
 
the patient is asymptomatic and no intervention is given, the treating MD is to document if the drop is 
expected for the patient in their environment. If the answer is no, then sites must document hypotension 
grade 1 on AE log. 
 
See CTCAE for grade 2-4 criteria. 
Sites are to use institutional standard practices to manage any adverse events that occur during or after 
vaccine administration (see table for management guidelines).  Sites may also use institutional practices 
prior to vaccine administration, such as hydration to abate adverse events. It is required however that 
the volume of the drug not be changed and the drug volume be 250mL. It is also required that the 
pre-medications be given per protocol section 4.1. Documentation on what patient was given to 
alleviate and manage events to be documented and submitted to BrUOG on CRF. 
 
Antibiotics post each dose ADXS11-001: 
 
All subjects will receive a 7 day course of either oral 80mg trimethoprim / 400 mg sulfamethoxazole once 
daily or 160 mg trimethoprim / 800 mg sulfamethoxazole (DS) three times over the course of the 7 days. 
Subjects with known allergy to sulfa drugs may receive ampicillin 500 mg four times daily for 7 days. 
Antibiotics will begin on Day 4 (approximately 72 hours) after each ADXS11-001 infusion.   
Antibiotics post last dose of ADXS11-001 or off study: All subjects who were consented to amendment # 
16 (or a later amendment) will be followed for 3 year Lm surveillance. The surveillance period will begin 
following the last dose of study treatment or at the time of study discontinuation. This period is intended 
to help ensure the eradication of Lm bacteria. This surveillance will include a 6 month course of either 
trimethoprim/sulfamethoxazole which will be initiated approximately 72 hours after the completion of the 
last dose of ADXS11-001or immediately following study discontinuation. 
Trimethoprim/sulfamethoxazole therapy should consist of either 160 mg trimethoprim/800 mg 
sulfamethoxazole (DS) tablet administered three times a week or 80 mg trimethoprim/400 mg 
sulfamethoxazole administered daily for 6 months. In subjects with a sulfa allergy, the 6 month course 
should consist of ampicillin 500 mg four times daily for 6 months, initiated approximately 72 hours 
following the last dose of study treatment or anytime upon discontinuation of study treatment.  
4.1.5 Lm Monitoring: 
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 (for patients who sign consent 
with amendment # 16 or later). This period is intended to help ensure the eradication of Lm bacteria.  
This surveillance monitoring phase will consist of the following: 
 
6 month course of oral antibiotics,  
 
CBC, chemistries, including CRP and ESR, every 4 months (+/- 2 weeks) 
 
Blood cultures every 4 months (+/- 2 weeks) 
This testing will be performed on all subjects who have received at least one dose of ADXS11-001 and 
who consented to amendment #16 (or later versions). Surveillance will occur every 4 months (±2 weeks) 
for 3 years beginning after the last dose of study treatment (ADXS11-001 or chemotherapy/radiation, 
whichever comes last). Institutional practice is to be followed for blood culture guidelines, but blood 
cultures are required to be drawn and results of cultures and all labs are required to be submitted to 
BrUOG. It is required that site submit location from where blood culture sample was drawn. 


3/28/16/pg. 23 
 
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.   
 
4.1.6 SUPPORTIVE CARE GUIDELINES: 
The major safety findings with ADXS11-001 occurring in >5% of subjects, as of January 2015 (n=230) 
and being possibly, probably or definitely related include anemia (7.8%), chills (33.9%), fatigue (11.7%), 
fever (24.8%), nausea (20.4%), vomiting (13.5%), headaches (15.7%), and hypotension (6.5%).  Most are 
Grade 1-2 in severity.  Subjects should receive appropriate supportive care measures as deemed necessary 
by the treating Investigator including but not limited to the items outlined below: 
4.1.7 CYTOKINE RELEASE SYMPTOMS: 
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, 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.  The 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 rare instances (~1%) grade 3-4 hypotension has 
been seen.  Therefore, close monitoring of blood pressure is strongly recommended at baseline, and 
during the post-infusion period. Increased levels of IL-6, 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 64-67 and are therefore recommended for cases of severe hypotension refractory to 
supportive care (e.g., fluids and/or pressors). 
 
 


3/28/16/pg. 24 
 
Recommended Management Guidelines for Adverse Events Associated with Cytokine Release 
Toxicity 
NCI 
CTCAE 
Grade or 
Severity 
Treatment 
Modification for Subsequent infusions 
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 
 
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. 
 Follow institutional standard of care for 
management 
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 


3/28/16/pg. 25 
 
Toxicity 
NCI 
CTCAE 
Grade or 
Severity 
Treatment 
Modification for Subsequent infusions 
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.[65-67] 


3/28/16/pg. 26 
 
4.1.8 Listeriosis and Listeria Infection - Identification and Management 
A person with wild type 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.[68]  Subjects may need immediate evaluation with a brain CT scan or MRI and a lumbar 
puncture with the analysis of spinal fluid to rule out meningitis. 
For symptomatic patients, diagnosis is confirmed only after isolation of Lm from a normally sterile site, 
such as blood or spinal fluid (in the setting of nervous system involvement), or amniotic fluid/placenta (in 
the setting of pregnancy). Stool samples are of limited use and are not recommended. Listeria 
monocytogenes can be isolated readily on routine media, but care must be taken to distinguish this 
organism from other Gram-positive rods, particularly diphtheroids. Selective enrichment media improve 
rates of isolation from contaminated specimens.  You can expect that the cultures will take approximately 
1-2 days for growth. Importantly, a negative culture does not rule out infection in the presence of strong 
clinical suspicion. Serological tests are unreliable, and not recommended at the present time. [68] 
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.  
4.1.9 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, such as ampicillin. 
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 (who consent to this study with amendment # 16 or later versions) will receive a 6 month 
course of an oral antibiotic regimen as a prophylactic measure following the completion of the last dose 
of ADXS11-001 treatment or at the time of study discontinuation. This additional safety measure is 
intended to eradicate Lm from the body.  
Lm surveillance monitoring will also be initiated following the completion of the last dose of ADXS11-
001 treatment or at the time of study discontinuation for all patients who are enrolled with amendment 
#16 (or later versions). This monitoring will include obtaining a blood sample for CBC, Chemistries, 
including CRP and ESR, and blood cultures for the detection of listeria. Institutional practice is to be 
followed for blood culture guidelines, but blood cultures are required to be drawn and results of cultures 
and all labs are required to be submitted to BrUOG. Testing will be performed on all subjects who have 
received at least one dose of ADXS11-001 and occur every 4 months (±2 weeks) for 3 years.  The 3 year 
time period will commence after the last study treatment patient receives on study (whether that be 
ADSX11-001 or chemotherapy/radiation) 


3/28/16/pg. 27 
 
Should a diagnosis of listeriosis be made at any point after treatment with ADXS11-001 and the 6 month 
course of oral antibiotics are 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 patients should be prepared and 
educational training performed.  
4.1.10 Concurrent therapies and procedures: All prescription and nonprescription medication 
(excluding vitamins, nutritional supplements and hormone replacement therapy) taken by the patient from 
30 days prior to screening and up to and including 30 days after the last administration of ADXS11-001 
(or chemotherapy or radiation whichever is given last) will be recorded in the medical record and on the 
concomitant CRF.  Any addition, deletion, or change in the dose of these medications will also be 
recorded during the study and 30 days post the last dose of ADXS11-001 or the last treatment with 
chemotherapy or radiation, whichever is last.  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 that are required per Lm monitoring 
are required to be captured on the CRF. If patients receive PI3K and TNF inhibitors it is required that 
this be added to the concomitant medication log. As a reminder these drugs are prohibited. 
Study subjects should be reminded that acetaminophen should not be used for pretreatment prophylaxis 
associated with the foreseeable adverse events related to the study drug 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 
of this trial: 
 
Anti-cancer systemic chemotherapy or biological therapy 
 
Surgical treatment as per consultation with the sponsor 
 
PI3K and TNF 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) 


3/28/16/pg. 28 
 
 
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. Pneumonia 
vaccine is 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. 
 
4.2 Chemotherapy  
5-FU: 1 gm/m2/day x 96 hours beginning on day 1-4 and day 29-32 + 7 days 
Mitomycin: 10 mg/m2, day 1 and 29 (day 29 can be + 7 days), dose should be capped at 20mg for patients 
with higher BSA’s  
 
Second cycle of chemotherapy (Day 29-32) (5-FU, Mitomycin) will not be administered unless ANC is ≥ 
1,500 and platelets are ≥ 100,000 
 
Chemotherapy will be administered as per institutional standard procedure. Chemotherapy for cycle 2 can 
not be held for more than 4 weeks for toxicity. Once radiation is completed no chemotherapy is to be 
given, therefore the second dose of chemotherapy may need to be omitted depending on toxicity. 
Chemotherapy is given concurrent with radiation.  
 
4.3 Radiation (IMRT)  
Note:  Intensity Modulated RT (IMRT) Is Mandatory. Tomotherapy Is Allowed. 
(For specific questions or concerns regarding this section please contact Dr. Lisa Kachnic at Boston 
University Medical Center by email:  lisa.kachnic@bmc.org or telephone:  617-638-7070)  
 
An anorectal atlas and guidelines to aid in contouring of clinical target structures can be found at 
http://www.rtog.org/pdf_file2.html?pdf_document=AnorectalContouringGuidelines.pdf 
Protocol treatment must begin within 21 days after protocol registration. 
 
4.3.1 
Dose Specifications  
4.3.1.1 Radiation treatment will be delivered once daily, 5 fractions per week.  All targets will be treated 
simultaneously. The treatment plan used for each patient will be based on an analysis of the 
volumetric dose, including dose-volume histogram (DVH) analyses of the PTV and critical 
normal structures.  An “inverse” planning method using dose-objective-based computerized 
optimization shall be used.  The treatment aim will be the delivery of dose to the PTVs and the 
exclusion of noninvolved tissue.  As in RTOG 0529, review of all DP-IMRT volume contouring 
and planning directives will be undertaken (this will be done retrospectively). Please send the 
plan to BrUOG via email at kayla_rosati@brown.edu, via fax at 401-863-3820 or via mail at the 
address below. Please make sure to email Kayla Rosati when plans are to be sent. 
BrUOG 
Division of Biology &Medicine 
Brown University 
Box GR001 
Providence, RI 02912 
 


3/28/16/pg. 29 
 
4.3.1.2 Target prescription dose:  The prescription dose scheme shall depend on staging as follows: 
 
4.3.1.3 For N0 disease:  The primary tumor PTV (PTVA) will receive 54 Gy in 30 fractions at 1.8 Gy 
per fraction.  The nodal PTVs will receive 45 Gy in 30 fractions at 1.5 Gy per fraction. 
 PTVA will receive 54 Gy in 30 fractions at 1.80 Gy per fraction. 
 PTV45 will receive 45 Gy in 30 fractions electively at 1.5 Gy per fraction and will include all 
nodal regions (mesorectum, presacral, obturators, interal iliac, external iliac and inguinal per the 
RTOG anorectal atlas, Myerson 2009). 
 
4.3.1.4 For N+ disease:  The primary tumor PTV (PTVA) and involved nodes PTV (PTV54) will 
receive 54 Gy in 30 fractions at 1.8 Gy per fraction.   
For example, if the right groin nodes are positive and the left groin and pelvic nodes are 
clinically negative, then the respective PTV doses are 54, 45, and 45 Gy in 30 fractions 
 PTVA will receive 54 Gy in 30 fractions at 1.8 Gy per fraction. 
 PTV45 will receive 45 Gy in 30 fractions electively at 1.5 Gy per fraction and will include all 
uninvolved nodal regions. 
 PTV54 will receive 54 Gy in 30 fractions at 1.8 Gy per fraction and will include all nodal  
regions containing involved nodes > 1cm in greatest dimension by CT/MRI or PET 
maximum standardized uptake value (SUVmax) uptake of 2.5 or greater. 
 
**** At 54 Gy, a further boost of 5.4 Gy to persistent and bulky gross disease plus 1.5 cm CTV and 0.5 
cm PTV margin may be provided at the discretion of the treating radiation oncologist, while maintaining 
the normal tissue radiation dose constraints provided in Section 4.3.1.6. 
 
4.3.1.5 Treatment schedule:  Treatment will be delivered once daily, 5 fractions per week (except for 
holiday weeks).  All targets will be treated simultaneously.  Breaks in treatment should be minimized. 
 
4.3.1.6 Dose specifications:   
The prescription isodose surface will encompass at least 90% of the primary and involved nodal PTVs, 
and at least 85% of the uninvolved nodal PTVs, reflecting the inherent difficulty of covering the shallow 
portions of these targets. 
 
No more than 5% of any PTV will receive < 95% of the prescription dose. 
 
No more than 2% of any PTV will receive < 90% of the prescription dose. 
 
No more than 2% of the primary PTV will receive > 115% of the prescription dose. 
 
4.3.1.7 Planning priorities:   
Tumor prescription goals followed by critical normal structure constraints are the most important 
planning goals. 
 
4.3.2 
Technical Factors 
Megavoltage equipment capable of delivering static intensity modulation with a multileaf collimator or 
dynamic intensity modulation (using a multileaf collimator or tomotherapy) is required.  Inverse-planned 
IMRT is required; conventional 3D CRT methods and forward-planned IMRT are excluded. 
 
4.3.2.1  Localization, simulation and immobilization 
4.3.2.2    A custom immobilization device (such as Alpha Cradle for supine patients and an Alpha Cradle 
with bowel displacement device for prone patients) is suggested to minimize set-up variability.  
Simulation will be done with the patient in the supine "arms up" or prone “arms up” position using a CT-
simulator with a slice thickness ≤ 5 mm.  It is strongly urged that patients be simulated in the prone 
position using bowel displacement techniques similar to those used for rectal cancer.  On RTOG 0529, all 
cases with major small bowel violation were planned in the supine position.  Oral and IV CT contrast is 
recommended, and an anal marker/wire at the verge or at the inferior extent of the tumor. Of note, daily 


3/28/16/pg. 30 
 
portal imaging is strongly encouraged for all patients. Additionally, consideration should be given to 
using the lightest couch top available to avoid unnecessary bolusing. Extra bolus on the inguinal skin is 
not typically necessary. For patients with macroscopic skin involvement, simulation should include 
placement of radio-opaque wires at the edge of visible/palpable skin involvement.  Bolus (either auto-
bolus or external bolus) must extend at least 2 cm beyond macroscopic disease.  If the tumor does not 
extend on the perianal skin, check TLDs (4.3.3.12) to see if any bolus is warranted.  
 
4.3.2.3   Treatment planning CT scans will be required to define gross target volume, and clinical target 
volumes.  The treatment planning CT scan should be acquired with the patient in the same position and 
using the same immobilization device as for treatment.  A description of the immobilization system used 
by each institution, patient position (supine or prone) and data regarding the range of positioning errors (if 
data exists) should be provided. 
 
4.3.2.4    All tissues to be irradiated must be included in the CT scan.  CT scan thickness should be 0.5 cm 
or smaller slices through the region that contains the primary target volumes.  The regions above and 
below the target volume may be scanned also with slice thickness of 0.5 cm. 
 
4.3.2.5   The GTV and CTV, and normal tissues must be outlined on all CT slices in which the structures 
exist. 
 
4.3.3   Treatment Planning/Target Volumes 
The definition of volumes will be in accordance with the 1993 ICRU Report #50: Prescribing, Recording 
and Reporting Photon Beam Therapy. 
 
4.3.3.1 The Gross Tumor Volume (GTV) is defined as all known gross disease determined from CT 
(and MRI or PET if performed), clinical information, digital exam, endoscopic findings and biopsy.  
There will be three GTVs: 
 
4.3.3.2 GTVA includes the gross primary anal tumor volume (as documented by digital exam, and as seen 
on CT, and PET or MRI if performed). To help define the cephalad extent of palpable disease it is 
strongly recommended that, at simulation, a thin flexible tube be placed either in the rectum or vagina 
with the tip of the tube at the level of the cephalad extent of palpable disease.   
 
4.3.3.3  GTVN54, including all nodal regions (as documented by biopsy or radiograph) which will 
receive 54 Gy. 
 
4.3.3.4  The Clinical Target Volume (CTV) is defined as the GTV plus areas considered to contain 
potential microscopic disease.  Three different CTVs will be defined, namely CTVA for the primary anal 
tumor volume; CTV45 for the elective nodal regions; and CTV54 for positive nodal regions. 
 
4.3.3.5  CTVA includes the gross primary anal tumor volume, the anal canal, and a 2 cm expansion into 
soft tissue and mesorectum, 1-2 cm into bladder, prostate, and gynecologic structures and none into bone 
and air.   
 
4.3.3.6   CTV45, CTV54 includes the nodal regions (respectively uninvolved, involved); uninvolved nodal 
regions should receive a 7 mm expansion around the vessels, while involved nodes should receive a 1.5 
cm expansion (except into uninvolved bone, genitourinary structures, muscles, or bowel). 
 
4.3.3.7   Nodal regions include:  
a. Mesorectal (including peri-rectal and presacral)  
b. Right and left inguinal 
c. Right and left external iliac 
d. Right and left internal iliac 


3/28/16/pg. 31 
 
Examples of the definitions of the appropriate nodal groups can be found on 
http://www.rtog.org/pdf_file2.html?pdf_document=AnorectalContouringGuidelines.pdf and in Ng M, 
Leong T, Chander S, Chu J, Kneebone A, Carroll S, Wiltshire K, Ngan S, Kachnic L: Australasian 
Gastrointestinal Trials Group (AGITG) Contouring Atlas and Planning Guidelines for intensity-
Modulated Radiotherapy in Anal Cancer. Int J Radiat Oncol Biol Phys 2012; 83(5): 1455-62. 
 
4.3.3.8  The Planning Target Volume (PTV) will provide a margin around the CTV to compensate for 
the variables of treatment set-up and internal organ motion.  A minimum of 5 mm around the CTV is 
required in all directions to define each respective PTV; 1 cm is recommended if daily pre-treatment 
image guidance with kV or cone beam is not performed. A nodal PTV should not be allowed to overlap 
with the primary PTVA, provided that their dose objectives are different, so that the maximum dose to the 
nodal PTV can be controlled in the optimization. 
 
4.3.3.9 Target volumes:  Target tumor volumes are delineated slice by slice on the treatment planning 
CT images.  The PTVs should spare non-target skin surfaces (manually or automatically trimmed to 3-5 
mm within the skin surface). 
 
4.3.3.10 Critical normal structures:  In addition, surrounding critical normal structures, including the 
femoral heads (right and left), bladder, external genitalia, iliac crest, small bowel, large bowel outside the 
CTVs, and perianal skin should be outlined. Bowel should be drawn as individual loops without the 
intertwining mesentery.  The normal tissues will be contoured and considered as solid organs.  The tissue 
within the skin surface and outside all other critical normal structures and PTVs is designated as 
unspecified tissue. 
 
4.3.3.11 Heterogeneity corrections:  All dose distributions shall include corrections for tissue 
heterogeneities.  The method used for heterogeneity calculations shall be reported. 
4.3.3.12 TLDs (thermoluminescent dosimeters) or diodes should be placed at the anal verge for at least 
one full treatment fraction to verify the planned dose to that region within 20% accuracy.  If TLDs are 
used, a set of at least 3 chips should be placed. 
 
4.3.4 Critical Structures  
 
4.3.4.1 Critical normal structures:  DVHs must be generated for all critical normal structures.   
NOTE: Effort should be made to achieve the listed dose constraints to normal tissues below. The dose 
constraints are listed in order from most to least important.  Major violations include > 5cc small bowel 
above 50 Gy, any point dose small bowel > 54 Gy, and > 5% femoral heads above 44 Gy. All other dose 
constraint deviations are considered minor violations but are acceptable for treatment. BrUOG and the 
Radiation Chair must be made aware of any violations in writing prior to radiation being administered if 
site believes they are unable to abide by radiation guidelines per protocol for a patient. 
 
4.3.4.2 Small bowel: 
 
No more than 200 cc above 30 Gy 
 
No more than 150 cc above 35 Gy 
 
No more than 20 cc above 45 Gy 
 
No more than 5 cc above 50.4 Gy 
 
Point dose > 54 Gy 
 
4.3.4.3 Femoral heads:   
 
No more than 50% above 30 Gy 
 
No more than 35% above 40 Gy 
 
No more than 5% above 44 Gy 
 


3/28/16/pg. 32 
 
4.3.4.4 Iliac crests:   
 
No more than 50% above 30 Gy 
 
No more than 35% above 40 Gy 
 
No more than 5% above 50 Gy 
 
4.3.4.5 External genitalia:   
 
No more than 50% above 20 Gy 
 
No more than 35% above 30 Gy 
 
No more than 5% above 40 Gy 
 
4.3.4.6 Bladder:   
 
No more than 50% above 35 Gy 
 
No more than 35% above 40 Gy 
 
No more than 5% above 50 Gy 
 
4.3.4.7  Large bowel:   
 
No more than 200 cc above 30 Gy 
 
No more than 150 cc above 35 Gy 
 
No more than 20 cc above 45 Gy 
 
4.3.5 Radiation Adverse Events 
4.3.5.1 Interruption of radiation during the treatment program is discouraged.  However, a rest period of 
≤ 7 days will be allowed for grade 4 skin reactions.  If radiation is held for > 7 days, the radiation Study 
Chair, Dr. Kachnic, or Dr. Christopher Crane, must be notified. 
 
4.3.5.2Radiation therapy must be held/interrupted for the following indications: 
 
ANC < 500/mm3 and/or platelets < 50,000: Radiation will resume when ANC > 500 and PLT > 
50,000. 
 
≥ Grade 3 diarrhea (≥ 7 stools/day above baseline):  Resume radiation when diarrhea is ≤ grade 2 
(< 7 stools/day above baseline).  Obtain electrolytes and creatinine  
 
Grade 4 dermatitis:  Radiation therapy can be resumed when dermatitis is < grade 3.  If RT is 
held for > 7 days, BrUOG, and the radiation Study Chairs, Dr. Kachnic, or Dr. Christopher 
Crane, must be notified.  Ulceration deemed to be due to tumor regression, rather than radiation 
dermatitis, is not a mandatory condition for holding treatment. 
 
Hold radiation therapy for ≥ grade 3 vomiting: Resume radiation therapy at < grade 2. 
 
If localized or generalized infection develops secondary to an area of confluent moist 
desquamation, radiation therapy will be held.  In this setting, radiation therapy will be resumed 
after there has been complete resolution of infection. 
 
Please note as an example: If radiation is held on day 29, chemotherapy on day 29 will also be held 
until radiation can be resumed.  
 
5.0 
TOXICITIES, DOSE MODIFICATIONS, AND MANAGEMENT 
Toxicities will be recorded as adverse events on the Adverse Event case report form and must be graded 
using The National Cancer Institute’s Common Toxicity Criteria (CTCAE) version 4.0 (Appendix C). 
 
 
 
 
 
 
 


3/28/16/pg. 33 
 
5.1 
Dose Modifications (Radiation, Mitomycin-C, 5-FU)  
(These dose modifications were utilized in the anal cancer study RTOG 0529) 
Note: Once reduced, drug doses must not be re-escalated to the original dose. 
Toxicity 
Parameters 
Agent 
Modificationc,d 
Diarrhea 
 
Grade 3 
1)5-FU 
2) RT 
1) Decrease dose 50%a 
2) Hold RT until diarrhea is 
< grade 2 
Grade 4 
1)5-FU 
2)RT 
1) Decrease dose 50%a, b 
2) Hold RT until diarrhea is 
< grade 2 
 
 
 
Mucositis/Stomatitis 
 
Grade 3 
1)5-FU 
1)Decrease dose 50%a 
Grade 4 
2)5-FU 
2)Decrease dose 50%a, b 
Rash: 
Dermatitis associated 
with radiation 
Grade 3 
1)5-FU 
2)RT 
1)Decrease dose 50% 
2)No required interruption 
of RT 
Grade 4 
1)5-FU 
2)RT 
1)Do not give the next cycle 
2) Hold RT until < grade 3 
ANC or Platelets 
 
 
Grade 3 
(ANC<1000) 
(Platelets<50,000)  
1)5-FU and mitomycin-C 
2)RT 
1)Decrease dose 50%e 
2)Hold RT; resume when 
ANC > 500 and PLT > 
50,000 
Grade 4 
(ANC<500) 
(Platelets <25,000) 
1)5-FU and mitomycin-C 
2)RT 
1)Decrease dose 50%b 
2)Hold RT; resume when 
ANC > 500 and PLT > 
50,000 
NOTE:  Second cycle of chemotherapy (5-FU, Mitomycin) will not be administered unless ANC is ≥ 1,500 and 
platelets are ≥ 100,000. Chemotherapy will not be held for more than 4 weeks secondary to toxicity.  
a. 
Obtain electrolytes and creatinine according to good medical practice, if not performed in previous 24 hours, and correct any 
electrolytic, renal, or volume abnormalities. These should have returned to baseline prior to any further chemotherapy being 
administered. 
b. 
Obtain CBC for any non-hematologic toxicity (including sepsis, fever, and bleeding) other than rash. In the presence of any non-
hematologic toxicity, use the most severe hematologic toxicity observed during cycle 1 (including during drug infusion, interval, 
incidental, or pre-treatment) in considering dosages for the second cycle as follows:  
Responses to modifications of 5-FU dosage are unpredictable due to genetic polymorphism (Dihydropyrimidine dehydrogenase, or 
DPD). If, in the investigator’s opinion it would not be in the best interest of the patient to continue with 5-FU after a grade 4 
adverse event because of the risk of repeated severe toxicity, further 5-FU should not be administered. Assessment of the patient 
should be based on the patient’s overall condition including consideration of each individual toxicity encountered. Consideration 
must include the duration of the toxicity in addition to its severity. In a study of patients experiencing severe toxicity from 5-FU, a 
correlation was shown between the sum of all the toxicity grades for mucositis, neutropenia, thrombocytopenia, diarrhea, and 
neurotoxicity (always graded 4 as neurotoxicity is a strong predictor for DPD deficiency) and measured DPD levels.28 Patients with 
any neurotoxicity or several concurrent grade 4 toxicities should not receive further 5-FU without a DPD assay. However, there is 
no absolutely safe level, and all patients require careful individual assessment. Women are more likely to have DPD deficiency than 
men. A thorough discussion should be conducted with the patient as to the possible risks and benefit of receiving further 5-FU.  
c. 
If a grade 4 toxicity occurs during the 96-hour infusion of 5-FU, the 5-FU must immediately and permanently be discontinued for 
that cycle. 
d. 
The second cycle of chemotherapy will not be administered until ANC is ≥ 1,500 and platelets are ≥ 100, 000. 
e. 
Based on pre-treatment counts, not interval counts. 
 
5.2 
ADXS11-001 Dose Modifications  
5.2.1  ADXS11-001 dose will not be reduced. 
The following criteria must be met to receive ADXS11-001: 
 
ANC > 1,000 cells/mm3,  
 
Platelets ≥ 50,000 cells/mm3,   


3/28/16/pg. 34 
 
 
Serum creatinine < 1.5 mg/dl  
 
All non-hematologic treatment related toxicities from chemoradiation have resolved to grade 2 or 
less. 
 
Patients experiencing any the following toxicities will be removed from the study and should not 
receive any additional ADXS11-001 unless review of a specific case with clinical rationale provides 
support for patient to remain on study (information must be submitted to BrUOG with enough 
time for extensive review of the case): 
 
Grade 4 treatment related toxicities lasting greater than 3 weeks 
 
Febrile neutropenia lasting > 7 days. 
 
Inability to administer full dose of intended radiation within a period of 14 weeks due to 
treatment related toxicities.  
 
Persistence of listeria bacteremia as documented by positive blood cultures for > 3 days (> 72 
hours).  
 
Document bacterial meningitis 
 
Clinical sepsis requiring pressors. 
 
5.2.2  Additional specific toxicities for ADXS11-001: 
5.2.2.1  Cardiovascular Toxicity:  
Patients with persistent grade 2-4 hypotension and/or grade 2 or 3 tachycardia (greater than 24 hours) 
with or without associated symptoms (e.g., syncope, dizziness, etc) despite optimal medical management 
may require a delay in subsequent therapy until recovered to grade 1. 
 
5.2.2.2  Persistent Listeria Infection: Patients who become persistently listeremic (defined by a positive 
blood culture for Listeria at greater than or equal to 72 hours after dosing), or for whom symptomatic 
treatment of the adverse event fails, will remain hospitalized until the infection has resolved with 
antibiotics. IV ampicillin is recognized as first line therapy for Listeria infection.  
Trimethoprim/sulfamethoxazole is second line, for penicillin-allergic patients.  In the event any patient 
fails to respond to ampicillin (or trimethoprim/sulfamethoxazole if allergic to penicillin), ciprofloxacin 
should be considered.  As a third line, oral amoxicillin or oral augmentin may be tried. Infectious Disease 
consultation may be helpful. Patients with persistent listeria bacteremia documented by persistently 
positive blood cultures for > 72 hours will be removed from study treatment. 
 
5.2.2.3  Hypersensitivity/Anaphylaxis/Infusion Site Extravasation: Grade 3 (or greater) toxicity 
requires prompt cessation of drug infusion and treatment of associated symptoms including 
bronchospasm, urticaria, hypotension, ulceration, and/or necrosis. Patients with this type of reaction will 
be removed from the study. Patients with such reactions occurring from treatment initiation with 
ADSX11-001 until 28 days post radiation will be replaced. Patients will be added to the same treatment 
schedule.  
 
 
 
 
 
 
 
 
 
 
 
 
 


3/28/16/pg. 35 
 
6.0 Schedule of Events 
For new patients 
who sign on to the 
study with 
amendment # 16 (or 
later versions) 
Prior to  
study 
entry/registration 
Prior to 
each tx 
with 
ADXS11-
001 
(within 
72 hours 
prior to 
dosing) 
0-3 
days   
pre-
RT 
Weekly 
during 
RTf 
1-2 weeks 
after 
completion 
of RT  
2-6 weeks after 
4th tx of 
ADXS11-001 
or if off study 
prior to 4th 
ADXS11-001, 
at time study 
discontinuation  
6 months 
post day 1 
chemo/RT 
Follow-up b 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History including 
all past surgeries 
< 14 days 
 
 
 
 
 
 
 
Concomitant medications 
(see section 4.1.10) 
Inclusive of 30 
days prior to 
drug 
X 
 
 
 
X 
 
X 
Physicale 
< 14 days 
X 
X 
X 
X 
X 
 
X 
Groin Examc 
< 42 days 
 
 
 
 
 
 
 
Diagnostic Biopsy 
anytime 
 
 
 
 
 
 
 
X-ray or CT or PET/CT of 
Chest 
< 42 days 
 
 
 
 
X 
 
XK 
CT or MRI or PET/CT of 
Abdomen & Pelvis 
< 42 days 
 
 
 
 
X 
 
XK 
ECOG performance status 
< 14 days 
X 
X 
X 
X 
X 
 
X 
CBC w/ diff, Platelets and 
ANC 
< 14 days 
Xd 
X 
X 
Xd 
X 
 
XL 
Serum creatinine 
< 14 days 
Xd 
X 
X 
Xd 
X 
 
 
Electrolytes(Na, K, Cl, 
Co2) 
< 14 days 
Xd 
X 
X 
Xd 
X 
 
XL 
ALT/AST/bilirubin 
< 14 days 
Xd 
X 
X 
Xd 
X 
 
 
Serum pregnancy test (if 
applicable) 
< 14 days 
 
 
 
 
 
 
 
PFTs with DLCO if 
history of clinically 
significant pulmonary 
disease 
< 6 weeks 
 
 
 
 
 
 
 
Cardiac echo for LVEF if 
history of clinically 
significant cardiac disease 
< 6 weeks 
 
 
 
 
 
 
 
HIV test 
< 14 days 
 
 
 
 
 
 
 
Adverse event evaluationa 
X 
X 
X 
X 
X 
X 
 
Xa 
Tumor evaluation by 
colonoscopy, 
sigmoidoscopy or  
proctoscopy 
<42 daysH 
 
 
 
 
 
 X (Bx if 
clinically 
indicated) 
12 months (6 months 
post 6 months scope) 
then annually for 5 
years. (Bx if 
clinically indicated)B 
Bx after chemo radiation 
and 4th tx of ADXS11-001 
 
 
 
 
 
 
6 monthsG 
 
Dispense/Prescribe Oral 
Prophylactic Antibiotics J 
 
X 
 
 
 
X 
 
X 
Disease and survival 
status 
 
 
 
 
 
 
 
X 
Lm Surveillance 
Monitoring 
 
 
 
 
 
 
 
XL 
A Patients will be followed for AE/SAE for 1 month (30 days) post last study drug (treatment on study). Post treatment 
assessment should not be done earlier than 30 days but may be done up to 1 week post 30 days. See section 11 for more details 
B Patients will be followed every 4 months (+/-2 weeks) for 3 full years post the last dose of ADXS11-001 or the final study 
treatment with chemotherapy/radiation (whichever is last) for Lm surveillance and follow-up assessments.  The follow-up portion 
will commence once patient comes off study (for patients who come off prior to receiving all 4 vaccines) or post the 2-6 week 
post the 4th treatment time point/visit. (For example if a patient comes off post vaccine #2, they will have the off study visit then 
commence follow-up 4 months later. If they complete study and all 4 vaccines, they will undergo an assessment 2-6 weeks post 
the 4th vaccine and then will start follow-up 4months later.) After 3 years, follow-up to be done annually year 4 and year 5 (year 4 
should be approximately 1 year after final 3 year post appointment and 5 year should be approximately 1 year after year 4 
appointment).   Follow-up is not required for patients who were registered then withdrew prior to any study treatment with 


3/28/16/pg. 36 
 
ADSX11-001. Tumor evaluation is not required for patients who came off study for disease progression or for patients who 
progress in follow-up.  
C clinical documentation of any groin adenopathy and lymphadenopathy (location: right vs. left; medial vs. lateral; mobile vs. 
fixed; and size)  
D Labs prior to ADXS11-001 are to be done within 72 hours of administration. If it is a Monday holiday an additional day is 
provided. Labs from screening can be used for ADXS11-001 #1 if within the 14 day window. 
E Physical exam may include anal exam. Physical exam, PS and AE evaluation from screening may be used for pre ADXS11-
001 #1 time point if done within the 14 day window. 
F Labs during weekly radiation must be done weekly. D29-32(+ 7 days) chemotherapy: labs will correspond with weekly 
radiation labs and a 72 hour window is also allowed prior to dosing. If there is a holiday an additional day is provided but this is 
to be documented. 
G If at 6 month time point (6 months post day 1 of chemo-radiation)  there is no residual suspicious tissue or if thought by 
physician to not be in the best interest of patient to biopsy, documentation of examination with reason for no biopsy to be sent to 
BrUOG to provide data for this time point. 
H If patient underwent anoscope this can be used for documentation. If patient is unable to tolerate any scope, reason must be 
documented and MRI can be used for disease measurements, distance and monitoring of disease response. Documentation of 
primary anal lesion size and distance from the anal verge to be sent regardless of type of scope or imaging at baseline. 
I Sigmoidoscopy, proctoscopy, colonoscopy to be used for assessment. Anoscope is allowed but is not preferred. Unlike follow-
up assessments, tumor evaluations are to be based on start date of chemotherapy/radiation. The 6 months tumor evaluation (and 
potential biopsy, see subscript H), is to be done 6 months post day 1 of chemo/RT. After this assessment, scopes are to be ordered 
as per institutional standard of care approximately  1 year (6 months post initial 6 month scope with bx if applicable) and then 
annually from last scope (with bx if applicable) for a total of 5 years. Therefore, if patient’s day 1 chemo/RT was January 1 2015, 
the 6 month scope would be due in July 2015. The 1 year scope would then be due 6 months later in January 2016. After this 
scope, the patient should be due annually. If more frequent scopes are ordered, BrUOG is to receive the results and information.  
J. All Subjects will receive a 37-day course of oral antibiotic therapy starting 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. All subjects will also receive an 
additional 6 month oral antibiotic course to be initiated 72 hours following the last dose of study treatment or anytime upon 
discontinuation of study treatment.  This course will consist of 80 mg trimethoprim/160 mg sulfamethoxazole once daily or 160 
mg trimethoprim/800 mg sulfamethoxazole (DS) tablet three times a week for 6 months. In subjects with 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 and the 6 month course should consist of ampicillin 500 mg four times daily 
initiated approximately 72 hours following the last dose of study treatment or upon discontinuation of study treatment. 
Antibiotics are required to be documented on the conmed log as well as the treatment form. 
K. For patients who come off study without progression, they will be assessed via CT or MRI or PET/CT of Abdomen & Pelvis 
and X-ray or CT or PET/CT of Chest every 6 months (+/- 1 month) until progression or up to 5 years. 
L. Lm Surveillance Monitoring will include a 6-month course of oral antibiotics and routine monitoring of CBC with differential 
and PLT, Chemistries (Na, K, Cl, Co2, serum creatinine, ALT/AST/bilirubin), CRP, ESR, and blood cultures.  Following 
completion of the last dose of study treatment or following study discontinuation all assessments will be performed every 4 
months (+/-2 weeks) for 3 years. 
 
Patient must begin trial within 21 days of registration 
 
Subject study participation: 
Each subject may participate in the study for up to 6 years from the time informed consent is signed 
through the final study contact.  This includes a study treatment phase, a 3 year post-ADXS11-001 
treatment Lm surveillance period which includes a prophylactic oral antibiotic administration phase (6 
months) and Lm surveillance monitoring approximately every 4 months for 3 years. All patients will be 
followed for disease and overall survival for 5 years post treatment as well. It is expected that a subject 
will participate in the study until the completion of the full 3 year Lm surveillance phase. However, 
following the completion of the 6 month oral antibiotic treatment, a subject will be eligible to participate 
in other investigational clinical studies.  
Reminder that patients may not and should not receive treatment with PI3K or TNFα inhibitors post this 
study treatment. If a patient is known to receive treatment with a PI3K or TNFα inhibitor BrUOG must be 
made aware via the concomitant medication log..  
 


3/28/16/pg. 37 
 
For patients who were previously consented and treated with ADXS11-001 on BrUOG 276 prior to 
amendment # 16 please see table below for follow-up schedule. It is very important that previously 
treated patients be re-consented via the consent addendum to ensure they are informed of the new 
information regarding possible delayed and late Listeria infection. Re-consent must be clearly 
documented and submitted to BrUOG and also kept in the patient shadow chart in the research office, to 
ensure compliance with study guidelines.  
Schedule of Events for patients 
who were consented and treated 
prior to amendment # 16 
At months  6, 12, then annually for 5 yearsa 
Physical 
X 
X-ray or CT or PET/CT of Chest 
X 
CT or MRI or PET/CT of 
Abdomen & Pelvis 
X 
ECOG performance status 
X 
Adverse event evaluationa 
X 
Tumor evaluation by 
colonoscopy, sigmoidoscopy or  
proctoscopy 
B 6 and 12 months then annually for 5 years. (Bx if clinically 
indicated) 
A. Patients will be followed for AE/SAE for 1 months post last study drug (treatment on study).  
Patients will be followed every 6 months for year 1 then annually for a total of 5 years. The follow-up portion will commence 
once patient comes off study or post the 2-6 week post the 4th treatment time point/visit. (For example if a patient comes off post 
vaccine #2, they will have the off study visit then commence follow-up 6 months later. If they complete study and all 4 vaccines, 
they will undergo an assessment 2-6 weeks post the 4th vaccine to commence follow-up 6 months later.) For patients who come 
off study without progression, they will be assessed via CT or MRI or PET/CT of Abdomen & Pelvis and X-ray or CT or 
PET/CT of Chest every 6 months (+/- 1 month) until progression or up to 5 years. Assessment time periods will not be adjusted 
based on out of window assessments. For example if a patient is due for imaging in January and then again July and the January 
imaging is not done until February, the next assessment is still due per study calendar in July. 
 
 
B. Sigmoidoscopy, proctoscopy, colonoscopy to be used for assessment. Anoscope is allowed but is not preferred. Unlike follow-
up assessments, tumor evaluations are to be based on start date of chemotherapy/radiation. The 6 months tumor evaluation (and 
potential biopsy, see subscript H), is to be done 6 months post day 1 of chemo/RT. After this assessment, the 1 year scope (and 
bx if applicable) is to be done 6 months later. The patient will then undergo annual scopes (and bx if applicable). Therefore, if 
patient’s day 1 chemo/RT was January 1 2015, the 6 month scope would be due in July 2015. The 1 year scope would then be 
due 6 months later in January 2016. After this scope, the patient would be due annually. Efforts to be made to keep patient on 
correct schedule and late or early assessments should not “reset” time frames for when scopes are due.. If more frequent scopes 
are ordered, BrUOG is to receive the results and information. Once a patient progresses additional scopes are not required per 
study. 
 
Schedule of vital sign monitoring  
 
 
Pre- 
Dose 
30 
minutes 
1 hour 
post 
Dose 
1.5 
hours 
2 
Hours 
Post 
Dose 
2.5 
hours 
3 
hours 
Post 
Dose 
3.5 
hours 
4 
Hours 
Post 
Doseb 
24 hours +/- 
2 hours 
72 hours +/- 
2 hours 
ADSX11-
001 
VSa 
VS 
VS 
VS 
VS 
VS 
VS 
VS 
VS 
VS + 
Toxicity 
Assessment 
VS + 
Toxicity 
Assessment 
a VS: Vital signs to include temperature, heart rate, blood pressure, and  respiration 
b the patient must have a temperature less than 38.5 degrees C/ 101.3 degree F 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. See section 
4.1.4  
(+/- 15 minutes given for all time points except 4 hours post which is only +15 minutes as patients must 
to be assessed a full 4 hours post vaccine) 
 
6.1 Laboratory Correlative Studies: 
Laboratory correlative studies may be performed on formalin-fixed, paraffin-embedded tumor specimens 
obtained during standard of care biopsies to evaluate for markers of immune response. Potential markers 
may include immunohistochemistry for T cell infiltration.  


3/28/16/pg. 38 
 
 
Formalin-fixed, paraffin-embedded tumor specimens may be evaluated for HPV-16 DNA with the use of 
the in situ hybridization–catalyzed signal-amplification method for biotinylated probes (GenPoint, Dako). 
HPV-16–negative tumors may be further evaluated for 12 additional oncogenic HPV types (18, 31, 33, 35, 
39, 45, 51, 52, 56, 58, 59, and 68) by means of a biotinylated-probe cocktail (GenPoint, HPV Probe 
Cocktail, Dako). An HPV-positive tumor will be defined as a tumor for which there was specific staining 
of tumor-cell nuclei for HPV in either analysis. Expression of p16 is an established biomarker for the 
function of the HPV E7 oncoprotein. Tumor p16 expression may be evaluated by means of 
immunohistochemical analysis with a mouse monoclonal antibody (MTM Laboratories) visualized with 
use of an autostainer (Ventana XT, Ventana) and a one-view secondary detection kit (Ventana). Positive 
p16 expression will be defined as strong and diffuse nuclear and cytoplasmic staining in 70% or more of 
the tumor cells.  
 
7.0  
Patient Assessments 
7.1  
Criteria For Evaluation And Endpoint Definitions 
 
7.2 
Measurement of Local Tumor  
Clinical complete response will be assessed by no disease on evaluation. Biopsy not required if physician 
does not feel there is any suspicious tissue to biopsy, however examination/scope to be completed and 
documentation no biopsy done secondary to MD decision for no suspicious tissue to be submitted to 
BrUOG.   
 
7.3  
Other Response Parameters  
 
7.3.1 
Progressive Disease:  
 
RECIST criteria for progressive disease: At least a 20% increase in the sum of the longest 
diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more lesions 
 
Local or regional progression by RECIST criteria must assessed with caution in patients with 
complete response by proctoscopy and biopsy since immunologic therapy may cause local 
inflammation or adenopathy. In these cases serial imaging is recommended prior to definitive 
determination of disease progression. 
7.3.2 
Second Primary Failure:  The appearance of second primary tumor 
 
7.3.3 
Disease-Free Survival (DFS):  Local-regional failure, appearance of distant metastases, 
appearance of a second primary and death due to any cause  
 
7.3.4 
Colostomy Failure:  For patients entering the study without a diverting colostomy, failure is a 
colostomy for any reason.  For patients entering the study with a diverting colostomy, failure is defined as 
one of the following:   
a. If the colostomy is reversed within 1 year from study entry, failure is a subsequent colostomy for 
any reason; 
b. If the colostomy is not reversed within 1 year, then it will be considered a colostomy failure at 
that time. 
 
7.3.5 
Colostomy-Free Survival:  Failure is a colostomy or death due to any cause. 
 
7.3.6 
Overall Survival:  Failure is death due to any cause. 
 
 
 


3/28/16/pg. 39 
 
8.0 
PATIENT REGISTRATION  
All patients will be registered through the Brown University Oncology Research Group Central Office. 
Eligibility Checklist with supporting documentation, and the signed Patient Consent Form must be faxed 
to the BrUOG Central Office, Fax: (401) 863-3820, at the time of registration and prior to patient 
treatment. 
 
Details of patient’s study participation should be documented in clinic/file notes. Registrations should be 
faxed to: 
Kayla Rosati 
Brown University Oncology Research Group, 
Fax: 401-863-3820 
Phone: 401-863-3000 
Kayla_Rosati@brown.edu 
 
 
All support data must be sent in with the corresponding BrUOG forms. 
It is the treating physician’s responsibility to review all data submitted to the BrUOG Central Office for 
accuracy and completeness and he/she must sign the off study form. Documentation and confirmation to 
be submitted to BrUOG to confirm all inclusion and exclusion criteria and for all assessments for 
registration in the schedule of evaluation table (section 6). 
 
9.0  
PHARMACEUTICAL INFORMATION 
9.1  
ADXS11-001 (IND #13,712) 
9.1.1 
Description: 
ADXS11-001 for infusion 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.    
 
9.1.2 
How Supplied, Storage and Stability:  
Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified 
on the label. 
ADXS11-001 will be supplied by Advaxis and distributed by Almac Clinical Services LLC.  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 
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.   
 
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.[1]  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. 


3/28/16/pg. 40 
 
 
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 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.  
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
 
9.1.3 
Safety Precautions: 
ADXS11-001 is classified a BSL-2, minimally pathogenic.  Precautions as stated in the BMBL 5th Edition 
include [74]: 
 
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 [50].  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 occur[ 75].  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)[76].     
 


3/28/16/pg. 41 
 
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.  
 
Precautions as stated in the BMBL 5th Edition50 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 Listeria 
monocytogenes in the clinical or research laboratory setting should be fully informed of the potential 
hazards associated with the organism, including potential risks to the fetus. 
 
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). 
 
9.1.4 
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.   
 
A dose of study drug is prepared in the following manner: 
 
Remove the appropriate number of vials from  -80± 10⁰ C and thaw the vials at room temperature for 
approximately 5-10 minutes.  Gently agitate mildly by hand to ensure that the drug is in suspension.  
Prepare the dose and infusion volume of ADXS11-001 as described below.   
 
ADXS11-001 (Drug Product concentration of 1.9x109 cfu/mL) 
 
To make a dose of 1.0x109 cfu:  Thaw 1 vial of 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 


3/28/16/pg. 42 
 
drug is in suspension.  Withdraw 0.53 mL of ADXS11-001 suspension and add it to the infusion bag for a 
final volume of approximately 250 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 in the source document (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).  NOTE: The 60 minute 
ADXS11-001 infusion at room temperature must be completed within 6 hours from product vial 
removal from the freezer.  
 
9.1.5 
Adverse Effects: 
ADXS11-001 is a live attenuated bioengineered nonpathogenic strain of Lm, and one that is known to 
stimulate a strong innate immune response characterized by high levels of cytokine release from immune 
cells into the general circulation.  This pattern of side effects is consistent with other immunotherapy 
agents. 
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). These symptoms usually present 
within 2-4 hours after the completion of infusions and are often mild to moderate and transient in nature 
or respond quickly to symptomatic treatment. In rare instances they may last up to 24 hours.  No 
cumulative 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. 
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. 
Please reference the ADXS11-001 IB for complete information regarding AEs. 
 
9.1.6 
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. 
 
9.1.6.1 Initial Requests: 
The designated person(s) from each participating hospital will complete the Drug Order Request Form 
and email the completed form to Almac and cc BrUOG.  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. 


3/28/16/pg. 43 
 
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 
Kayla Rosati at: Kayla_Rosati@brown.edu  
 
9.1.6.2  Subsequent Requests: 
If additional drug is needed, please email a “Drug Order Request Form” to Almac as noted above.   
 
Please note that study drug is shipped at -70oC and has a TempTale4 (temperature monitor) included 
in the box.   It is imperative that all study drug shipments be stored at - 80 ± 10°C immediately after 
being removed from the shipping container. 
 
Cold Chain Verification.  Cold chain verification must be completed immediately before unpacking the 
shipper, by carefully following the instructions below:   
 
 


3/28/16/pg. 44 
 
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. 
No study drug should be administered to any patients unless the TempTale USB4 has been 
reviewed and the shipment has been verified or authorized for clinical use.  
 
For questions about TempTale USB4 and drug shipments, please e-mail the following: 
Almac: palogistics.clinicalservices@almacgroup.com 
CC: 
larry.haines@almacgroup.com 
  
logistics@advaxis.com 
 
Kayla_rosati@brown.edu 
Display 
Stop Button 
USB Adapter & 
Cable 


3/28/16/pg. 45 
 
9.1.7 
Drug Accountability: All study drug must be accounted for by using the NCI Drug 
Accountability Form during the course of this study. The pharmacist or qualified research staff member 
will maintain inventory records.  The records will include details of materials received, the date dispensed, 
the patient identification number and initials of patient receiving the dose, , and documentation of drug 
destruction following notification from the Sponsor or completion/termination of the study.  Receipt and 
dispensing of trial medication must be recorded by an authorized person at the trial site.  It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and institutional 
guidelines and procedures, and provided that appropriate records of disposal are kept. 
 
9.1.8 
Drug Destruction and Return:   
Opened and unopened vials can be destroyed according to the site’s guidelines for Biohazard Waste 
Disposal or by using the steps shown below for ADXS11-001 destruction.   
 
The used or unused vials of ADXS11-001 can be treated with a 10% bleach solution for disinfection.  Use 
a 10% solution of Clorox (or any similar commercial chlorine bleach solution containing 5.25% sodium 
hypochlorite (NaClO) for disinfection. 
 
1. Treat unopened or opened vials(s) with a minimum volume  
of 0.25 mL of bleach solution to 
sterilize its contents. 
2. Empty the disinfected chemical solution in drain, run water to remove residual materials from 
drain and discard empty vials into designated biohazardous waste container, as applicable. 
3. The residual IV bags or other components used for preparing the drug product should also be 
inactivated with bleach and discarded in similar manner as explained in steps 1 and 2. 
 
If ADXS11-001 is destroyed at the site, 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: 
 
BrUOG has been alerted to drug destruction and has been sent hospital destruction policy 
 
written authorization for disposal/destruction has been granted by Advaxis 
 
arrangements have been made for the disposal 
 
appropriate records of the disposal have been documented 
 
A separate NCI Drug Accountability Form must be completed for Drug Destruction and submitted 
to BrUOG. 
 
9.1.9 
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). 


3/28/16/pg. 46 
 
9. Inform the Principal Investigator (PI) and other appropriate personnel, e.g. Research Manager, 
Pharmacy Manager. 
 
9.1.10 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. 
 
9.2 
5-Fluorouracil (5-FU): Refer to package insert for additional information 
 
9.2.1 
Dose Formulation:  5-FU is a marketed drug available as 50 mg/ml in 10, 50 or 100 ml vials as a 
colorless to faint yellow preservative free aqueous solution, with pH adjusted to approximately 9.0 with 
sodium hydroxide.  Compatible with NS, D5W.  Administration of 5-FU should be only by the 
intravenous route taking care to avoid extravasation.  Direct administration is over 1-2 minutes, or 
intermittently in 50-100 ml minibag over 20-30 minutes, or by continuous infusion (in 1 L normal saline 
or ambulatory infusion pump) which has the best therapeutic index.  Vein pigmentation and 
thrombophlebitis may be seen distal to infusion sites.  For continuous infusion a central venous access 
device is preferred.  Compatible with heparin and leucovorin but not with ondansetron. 
 
9.2.2 
Pharmacology:   
It is a fluorinated pyrimidine antimetabolite.  5-FU resembles the natural uracil molecule in structure, 
except that a fluorine atom has been substituted for a hydrogen atom in the 5 position.  T½ is 8-13 minutes.  
It is distributed in all body water by passive diffusion and crosses the placenta.  There is evidence that the 
metabolism of fluorouracil in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid 
to thymidylic acid.  5-FU generates fluorinated nucleotides (FdUMP, FUTP), which interfere with the 
synthesis of DNA and to a lesser extent inhibit the formation of ribonucleic division and growth by 
incorporation into RNA.  The effect of fluorouracil may be to create a thymidine deficiency which 
provides unbalanced growth and death of the cell.  Catabolism is via hepatic and extrahepatic routes via 
DPD to dehydrofluorouracil (DHFU), which is subsequently metabolized to fluoro-β-alanine (FBAL).  
Excreted as respiratory CO2, only 5% being excreted unchanged in the urine.  Administration should be 
avoided in the presence of hepatic dysfunction. 
 
 


3/28/16/pg. 47 
 
9.2.3 
Supplier:   
5-FU is available commercially.  Generic forms are available. 
 
9.2.4 
Storage:   
Although 5-FU solution may discolor slightly during storage, the potency and safety are not adversely 
affected.  Store at room temperature (49°-86°F) and protect from light.  If a precipitate occurs due to 
exposure to low temperatures, resolubilize by heating to 140°F (60oC) with vigorous shaking; allow to 
cool to body temperature before using.  Discard after 8 hours once vial is opened.  Discard if yellow 
coloration is marked since this indicates decomposition.  Stable in D5W for 30 days in plastic syringes at 
room temperatures.  In portable infusion pump reservoirs 5-FU is stable for up to 7 days but precipitation 
may occur at low temperatures. 
 
9.2.5 
Side Effects and Toxicities:   
Immediate side effects include mild nausea and vomiting (common), lacrimation, conjunctivitis, angina, 
arrhythmia, radiation recall and anaphylaxis (rare). Early onset effects include stomatitis and 
esophagopharyngitis (which may lead to sloughing and ulceration), diarrhea with cramping and/or 
bleeding, and anorexia.  Leukopenia usually follows every course of adequate therapy with fluorouracil.  
The lowest white blood cell counts are commonly observed between the 9th and 14th days after the first 
dose, although uncommonly the maximal depression may be delayed for as long as 20 days.  By the 30th 
day the count has usually returned to the normal range.  Megaloblastosis may occur.  Alopecia (usually 
mild) and dermatitis may be seen.  The dermatitis most often seen is a pruritic maculopapular rash usually 
appearing on the extremities and less frequently on the trunk.  Other side effects include myocardial 
ischemia, lethargy, malaise, headache, allergic reactions, neurotoxicity (disorientation, confusion, 
euphoria, dizziness, incoordination-acute cerebellar syndrome, encephalopathy), visual changes, 
photosensitivity (eyes and skin), nail changes including loss of nails, skin thickening, cracking, dryness or 
sloughing, biliary sclerosis, or acalculous cholecystitis.  Hand foot syndrome (palmar plantar 
erythrodysesthesia) is more common with continuous infusion.  Late effects may include tear duct fibrosis 
and neurotoxicity. See 7.4.1 for more information on decreased tolerance 5-FU and the management of 
toxicity.  
9.3 
Mitomycin-C 
Refer to package insert for additional information 
 
9.3.1 
Dose Formulation:  
 Each vial contains either mitomycin-C 5 mg and mannitol 10 mg or mitomycin-C 20 mg and mannitol 40 
mg.  To administer, add sterile water for injection, 10 ml or 40 ml respectively to a concentration of 0.5 
mg per ml.  Shake to dissolve.  If product does not dissolve immediately, allow to stand at room 
temperature or shake vial under warm tap water for 2 minutes to assist dissolution.  Reconstituted 
mitomycin is a clear blue or purple solution.  If reconstituted to higher concentrations (1-2 mg/ml) avoid 
low temperatures because crystals may form. 
 
Mitomycin-C should be given intravenously only, using care to avoid extravasation (severe, see Appendix 
V).  Give as slow push through sidearm of free flowing i.v. at 1.5 mg/3 ml per minute.  May be mixed in 
50-100 ml minibag over 10-30 minutes. 
 
9.3.2 
Pharmacology:   
Mitomycin-C is an antibiotic with alkylating agent properties cross-linking guanine and cytosine, which 
selectively inhibits the synthesis of deoxyribonucleic acid (DNA) and degrades preformed DNA.  This 
results in nuclear lysis and formation of giant cells.  At high concentrations of the drug, cellular RNA and 
protein synthesis are also suppressed.  Non-phase specific, but has maximum effects in late G1 and S. 
 
In humans, mitomycin, which acts as a pro-drug is rapidly cleared from the serum after intravenous 
administration.  It is distributed in kidneys, muscles, heart, lungs, intestines and ascites; and enters breast 
milk.  The time required to reduce the serum concentration by 50% after a 30 mg bolus injection is 17 


3/28/16/pg. 48 
 
minutes.  After injection of 30 mg, 20 mg, or 10 mg i.v., the maximal serum concentrations were 2.4 
mcg/ml, 1.7 mcg/ml, and 0.52 mcg/ml, respectively.  Clearance is affected primarily by metabolism in the 
liver, but metabolism occurs in other tissues as well.  The rate of clearance is inversely proportional to the 
maximal serum concentration likely due to saturation of the degradative pathways. 
 
Approximately 10% of a dose of mitomycin-C is excreted unchanged in the urine.  Since metabolic 
pathways are saturated at relatively low doses, the percent of a dose excreted in urine increases with 
increasing dose.  Small amounts are also found in the bile and feces. 
 
Administer with caution in the presence of impaired liver or renal function. 
9.3.3 
Supplier:  Mitomycin-C is available commercially.  Generic forms are available. 
 
 
9.3.4 
Storage: 
1. Unreconstituted:  Mitomycin-C is stable for the lot life indicated on the package.  Store at 
room temperature.  Avoid excessive heat (over 40°C) and keep away from light. 
2. Reconstituted Mitomycin-C is stable for 14 days refrigerated or 7 days at room temperature 
(up to 30oC).  Higher concentrations than 0.5 mg/ml may degrade and precipitate if stored. 
3. Compatible with D5W, NS and Ringer’s lactate Diluted in various i.v. fluids at room 
temperature, to a concentration of 20 to 40 micrograms per ml: 
IV Fluid 
Stability 
5% Dextrose Injection 
3 hours 
0.9% Sodium Chloride Injection 
12 hours 
Sodium Lactate Injection 
24 hours 
 
 
9.3.5 
Side Effects and Toxicity 
Immediate effects may include vein irritation, mild nausea and vomiting (1-2 hours) and bronchospasm 
(4-12 hours). 
 
Early toxicities include thrombocytopenia and leukopenia which are cumulative.  Nadir occurs at 24-28 
days, with recovery at 42-56 days.  Deaths due to septicemia have been reported.  Stomatitis is frequent 
but mild, alopecia is rare.  Rashes are rare and blue bands may be seen in the nails.  Mitomycin may also 
cause dyspnea with cough and radiographic evidence of pulmonary infiltrate.  A few cases of adult 
respiratory distress syndrome (interstitial pneumonitis) have been reported; also fever, anorexia, fatigue, 
blurred vision, amenorrhea, edema, thrombophlebitis, hematemesis, elevated LFTs or diarrhea may occur.  
CNS effects may include syncope and rarely acute encephalopathy. 
 
Delayed toxicities (weeks to months) include chronic pulmonary fibrosis, erythema and/or ulceration 
occurring either at or distant from the injection site, rising creatinine, microangiopathic hemolytic anemia, 
and renal failure. 
 
Note:  Mitomycin is a vesicant and cellulitis, necrosis, ulceration and consequent sloughing of tissue may result if 
the drug is extravasated during injection (see Appendix V). 
 
10.0 Agent Accountability 
Agent Inventory Records – The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of all agents received from manufacturer using 
a Drug Accountability Record Form.   
 
10.1 Treatment compliance 
Records of study medication used, dosages administered, and intervals between visits will be recorded 
during the study. Drug accountability will be noted. 


3/28/16/pg. 49 
 
All drugs will be administered to eligible patients under the supervision of the investigator or identified 
sub-investigator(s).  The pharmacist will maintain records of drug receipt drug preparation, and 
dispensing, including the applicable lot numbers. Any discrepancy between the calculated dose and dose 
administered and the reason for the discrepancy must be recorded in the source documents. 
 
11.0 Adverse Drug Reaction (ADR) Reporting  
U.S. regulations require that a sponsor reports Serious Adverse Events (SAEs) occurring with use of its 
product in a clinical trial if it is unexpected, and felt to be related to use of the drug.  During the conduct 
of Investigator Sponsored Trials (ISTs), where the investigator holds the Investigational New Drug (IND) 
application, all SAEs that occur will be evaluated by the investigator for reportability to FDA. An 
Adverse Event should be identified, Serious Adverse Event and Expectedness determined and causality 
assessed by the investigator using the definitions that follow. 
 
Intensity for each adverse event will be scored using CTCAE Version 4.0.  A copy of the CTCAE 
Version 4.0 can be downloaded from the CTEP homepage (http://ctep.info.nih.gov).  All appropriate 
treatment areas have access to a copy of the CTCAE Version 4.0.   
 
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.  All AEs and SAEs will be recorded from the time the 
consent form is signed through the 3-year Lm surveillance period of the study and at each examination on 
the AE CRF as described below.  The reporting timeframe for AEs meeting any serious criteria is 
described in Section 11.1 below. 
 
11.1 Definitions 
An Adverse Event is any untoward medical occurrence in a patient administered a pharmaceutical 
product and which does not necessarily have to have a causal relationship with the treatment.  For 
marketed products in the U.S., a Serious Adverse Event is an adverse event occurring at any dose that 
results in any of the following outcomes: 
 
Death 
 
Life-threatening1 
 
Persistent or significant disability/incapacity2 
 
In patient hospitalization or prolongation of existing hospitalization: Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an AE. 
 
Congenital anomaly/birth defect 
 
An event may not meet any of the above seriousness criteria but still be judged as medically serious.  
That is, important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes (a-e) listed above.  Some examples of this type of event are: 
 
blood dyscrasia without inpatient hospitalization 
 
convulsions without inpatient hospitalization 
 
intensive treatment in an emergency room or at home for allergic bronchospasm without inpatient 
hospitalization 
 
development of drug dependency 
 
drug abuse 
                                                           
1 The term "life-threatening" in the definition of "serious" refers to an event in which in the view of the initial reporter     the patient was at 
immediate risk of death from the adverse experience as it occurred; it does not refer to an event which had it occurred in a more severe form, 
might have caused death. 
2 A substantial disruption of a person’s ability to conduct normal life functions. 


3/28/16/pg. 50 
 
 
overdose 
with 
an 
associated 
serious 
event, 
or 
required 
intervention 
to 
prevent 
impairment/damage 
 
An Unexpected Adverse Event is not listed in the current US Package Insert (USPI) or an event that 
may be mentioned in the USPI, but differs from the event because of greater severity or specificity.  
 
Causality is a determination of whether there is a reasonable possibility that the drug may have caused or 
contributed to an adverse event. It includes assessing temporal relationships dechallenge/rechallenge 
information, association (or lack of association) with underlying diseases, and the presence (or absence) 
or a lack of one or more likely causes. 
The Investigator must determine if an adverse event is in some way related to the use of the study drug.  
This relationship should be described as follows: 
 
 
Unlikely: The event is clearly due to causes distinct from the use of the study drug, such as a documented 
pre-existing condition, the effect of a concomitant medication, a new condition which, based on the 
pathophysiology of the condition, and the pharmacology of the study drug, would be unlikely related to 
the use of the study drug. 
 
 
Possible: The event follows a reasonable temporal sequence from administration of the study drug or the 
event follows a known response pattern to the study drug BUT the event could have been produced by an 
intercurrent medical condition which, based on the pathophysiology of the condition, and the 
pharmacology of the study drug, would be unlikely related to the use of the study drug or the event could 
be the effect of a concomitant medication 
 
 
Probable: The event follows a reasonable temporal sequence from administration of the study drug and 
the event follows a known response pattern to the study drug AND the event cannot have been reasonably 
explained by an intercurrent medical condition or the event cannot be the effect of a concomitant 
medication 
 
 
Definite: The event follows a reasonable temporal sequence from administration of the study drug, the 
event follows a known response pattern to the study drug and based on the known pharmacology of the 
study drug, the event is clearly related to the effect of the study drug 
 
 
Unknown: Based on the evidence available, causality cannot be ascribed 
 
For both serious and non-serious adverse events, the investigator or sub-investigator must determine both 
the intensity of the event and the relationship of the event to drug administration. 
 
Any serious adverse event occurring after the patient has provided informed consent and until 4 weeks 
after the patient has stopped study participation (last date of treatment) must be reported. This includes 
the period in which the study protocol interferes with the standard medical treatment given to a patient 
(e.g. treatment withdrawal during washout period, change in treatment to a fixed dose of concomitant 
medication). 
 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse experiences 
will be forwarded to the product manufacturer by the investigator 
 
11.2 Recording and Reporting: Serious Adverse Events Reportable to the FDA 
In the context of an Investigator Sponsored Trial being conducted under an IND, CFR 312.32 states the 
FDA needs to be informed of unexpected and related SAEs (SUSARs) as soon as possible or within 15 
calendar days. In addition, the investigator must notify the FDA of any unexpected, fatal or life-
threatening experience associated with the use of the drug as soon as possible, or within 7 calendar days 
by telephone or facsimile.   


3/28/16/pg. 51 
 
 
When the principal investigator has determined that a Serious Adverse Event requires reporting to the 
FDA (unexpected and possibly related to study drug), the following actions must be completed: 
 
Actions towards FDA:  
Sites: All events must be reported, by FAX to Brown University Oncology Research Group.  
 
BrUOG: The BrUOG Central Office will notify by phone and/or fax all drug reaction reports to the FDA, 
Advaxis, the Principal Investigator, and the participating sites (who will in turn notify their local IRBs) 
who will report all SAEs to Advaxis regardless of relationship with any study drug or expectedness 
within 24 hours of learning of its occurrence but no later than 7 days. The BrUOG Central Office will 
report all unexpected and related SAEs (SUSARs) to Advaxis and their Pharmacovigilance CRO within 
24 hours of learning of its occurrence but no later than 7 days. 
 
Sites: All sub-investigators must report all SAEs to the investigator-sponsor so that the investigator-
sponsor can meet his/her foregoing reporting obligations. This includes serious, related, labeled 
(expected) and serious, related, unlabeled (unexpected) adverse experiences.  
 
BrUOG: Serious unexpected adverse events will be reported as an amendment to the IND within 15 days 
of sponsor notification. They will all receive a simultaneous copy via facsimile of all adverse events filed 
with the FDA. A copy of the form will be kept by the BrUOG Central Office.   
 
Sites: All deaths during treatment or within 30 days following completion of active protocol therapy 
(treatment) must be reported within 5 working days of being made aware of the event. For SAEs 
that are thought to be related to drug or for deaths thought to be even possibly related to drug, 
within 24 hours of being made aware of the event (when possible), but no later than 5 business days.  
 
30 days post last dose of treatment: All deaths or SAEs that are thought to be potentially related to 
the ADXS11-001 drug or SAEs with any potential link to Listeria are to be reported to BrUOG 
within 5 days of the site being made aware of the event. AEs that are not serious during this time 
frame do not need to be reported to BrUOG. See 11.2.1 #5 
 
11.2.1 Site responsibility when reporting an FDA action 
The principal investigator is also responsible for providing all Serious Adverse Events (on the OBA form) 
to the BrUOG office who will submit to the FDA and Advaxis on behalf of the site. The BrUOG office 
will in return send a formal letter to all sites participating regarding each event. It is then the 
responsibility of each participating site to submit to the IRB on record as per their local IRB policy. This 
applies to initial and follow-up information. 
1. Telephone report: For SAE’s, both initial and follow-up, contact BrUOG Central Office (401) 
863-3000 within 24 hours of being made aware of the event and PRIOR to submitting any reports 
to BrUOG.  For SAEs BrUOG will contact Advaxis within 24 hours of being made aware of the 
event, but no later than 7 days with the completed SAE report. 
2. Complete the OBA Adverse Event Page (Appendix H) 
OBA Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description of the OBA 
form: 
 
Treatment regimen (dosing frequency, combination therapy) 
 
Protocol description (and number, if assigned) 
 
Description of event, severity, treatment, and outcome, if known 
 
Supportive laboratory results and diagnostics 


3/28/16/pg. 52 
 
 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication (ADXS11-001, Mitomycin, 5-FU, radiation) 
3. Attach the photocopy of all applicable examinations, medical notes and records related to the 
Serious Adverse Event and document the dates these were made. For laboratory results, include 
the laboratory normal ranges. For hospitalizations, Admission H&P, Discharge Summary, 
Consultative reports, etc. could be very helpful. In the case of a Fatal event, provide an autopsy 
report, when it becomes available 
4. Sites to send the completed OBA Serious Adverse event page to the BrUOG office no later 
than 5 business days from site being made aware of the event. For SAEs that are thought to 
be related to drug or for deaths thought to be even possibly related to drug, within 24 hours 
of being made aware of the event (when possible), but no later than 5 business days. 30 days 
post last dose of treatment: All deaths or SAEs that are thought to be potentially related to 
the ADXS11-001 drug or SAEs with any potential link to Listeria are to be reported to 
BrUOG within 5 days of site being made aware of the event. 
5. Post 30 day AE assessments all patients & for 3 year safety observation period (for patients 
who enroll to amendment # 16 or later versions): 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 all patients 
including 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 BrUOG or any other authority. 
 
Brown University Oncology Research Group (BrUOG) Central Office, 
Phone:  (401) 863-3000, 
Fax:  (401) 863-3820 
Cell: (401) 413-5844 
Kayla_Rosati@brown.edu 
11.2.2 BrUOG responsibility for reporting: 
1. To review all materials received from sites 
2. Telephone the FDA immediately (day of awareness), in the case of reportable death or life-
threatening events 
3. Fax completed OBA form to the FDA and mail when appropriate within the timelines mentioned 
above    
 
 
FDA CBER 
10903 New Hampshire Avenue, Building 71, G112, Silver Spring, MD 20993 
Fax division fax: 1-301-595-1303 and OBA fax at 301-496-9839  
 As well as sending the SAE to Center for Biologics Evaluation and Research as an amendment to 
the IND) 
 
BrUOG will also send the OBA SAE form to OBA via their requirements. 
 
The Brown University Oncology Research Group will provide a copy of the information sent to FDA by 
email within 24 hours, but no later than 7 days, after being made aware of the SAE to the following 
Advaxis responsible parties: 
 
Advaxis PV CRO (for SUSARs only)- serious unexpected and related to ADXS11-
001:  i3drugsafetyPV@inventivhealth.com or    FAX: 866-880-9343  
 
Advaxis 
Pharmacovigilance 
(for 
all 
SAEs 
including 
SUSARs):  
APV_BrUOG276@advaxis.com 
 
In addition, all SAEs shall be sent to Advaxis on an ongoing basis. 
 


3/28/16/pg. 53 
 
Results of any relevant complementary exams performed to obtain the final diagnosis of any SAE (e.g. 
hospital discharge summary, autopsy report, consultations, etc.) will be made available to Advaxis upon 
request. 
 
11.2.3 Follow-up Reports 
Additional Info may be added to a previously submitted report by any of the following methods. 
 
Adding to the original OBA report and submitting it as follow-up 
 
Adding supplemental summary information and submitting it as follow-up with the original OBA 
form  
 
Summarizing new information and faxing it with a cover letter including subject identifiers (i.e. 
D.O.B. initial, subject number), protocol description and number, if assigned, suspect drug, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted  (The subject identifiers are important so that the new information is added to the 
correct initial report). 
 
The investigators should take all appropriate measures to ensure the safety of the subjects. 
Notably they should follow-up to determine the outcome of any Adverse Events (clinical signs, 
laboratory values or other, etc.) until the patient has recovered, abnormal values have returned to 
normal or until progression has been stabilized. This may imply that follow-up will continue after 
the subject has left the study and that additional investigations may be necessary.  
 
In the case of a Death or a Life-threatening event, the investigator should provide a follow-up 
report, with positive or negative findings within 5 business days of the awareness of the initial 
observation.  
 
Any reportable Serious Adverse Events brought to the attention of the Investigator at any time 
after cessation of the trial and considered by him/her to be reasonably associated with medication 
administered during the period should also be submitted to the FDA.  A copy should be provided 
to Advaxis, if an Advaxis product was involved or the appropriate manufacturer of another 
product within 24 hours after FDA submission (see above). 
 
The OBA form, which will provide follow-up information about a reportable SAE must be submitted to 
the BrUOG office who will then send all information to the appropriate parties (FDA, Advaxis, the 
Principal Investigator, and the participating sites (who will in turn notify their local IRBs). 
 
11.3: Safety Reporting for IND Holders 
In accordance with 21 CFR 212.32, Sponsor-Investigator of the study conducted under an IND must 
comply with following safety-reporting requirements:  
 
11.3.1:  Expedited IND Safety Reports: 
7 Day calendar Telephone or Fax Report:  On behalf of the Sponsor-Investigator BrUOG is required to 
notify the FDA of any that is serious, unlisted/unexpected and assessed by the investigator to be possibly 
related to the use of study drug(s).  An unexpected adverse event is one that is not already described in the 
Investigator Brochure.  Such reports are to be telephoned or faxed by the sites to Brown University 
Oncology Research Group (BrUOG) who will then fax the information to the FDA as well as report to 
Advaxis as soon as possible but no later than 7 calendar days of first learning of the event.  
 
Brown University Oncology Research Group (BrUOG) Central Office, 
Fax:  (401) 863-3820 
 
BrUOG will then fax the information received to the number below: it will be directed to the FDA 
division fax in the Center for Biologics Evaluation and Research at 
 
FDA fax number for IND/OBA Safety Reports:  
FDA: 1-301-595-1303 and OBA fax at 301-496-9839  


3/28/16/pg. 54 
 
 
 
All written IND/OBA Safety Reports submitted to the FDA by the Sponsor-Investigator must also be sent 
to Advaxis. 
 
AND: Report of Adverse Events to the Institutional Review Board 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) of a serious 
adverse event according to institutional policy.   
 
11.4: Adverse event updates/IND safety reports 
Brown University Oncology Research Group, and Advaxis shall notify the Investigator via an IND Safety 
Report of the following information: 
 
Any AE associated with the use of study drug in this study or in other studies that is both serious 
and unexpected. 
 
Any finding from tests in laboratory animals that suggests a significant risk for human subjects 
including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and unexpected AE(s) or 
significant risks to subjects. 
 
11.5:  IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the Sponsor-Investigator shall within 60 days of the 
anniversary date that the IND went into effect submit a brief report of the progress of the investigation.  
Please refer to Code of Federal Regulations, 21 CFR § 312.32 for a list of the elements required for the 
annual report.  All IND annual reports submitted to the FDA by the Sponsor-Investigator should be 
copied to Brown University Oncology Research Group, Advaxis and assigned Clinical Science Liaison.   
 
12.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
Patients will be informed that they have the right to withdraw from the study at any time for any reason, 
without prejudice to their medical care. Extraordinary medical circumstances or withdrawal of consent by 
the patient: If, at any time, the constraints of this protocol are detrimental to the patient's health, and/or the 
patient no longer wishes to continue protocol therapy, the patient shall be withdrawn from protocol 
therapy.  Patients will also be withdrawn from study for the following reasons: 
 
Disease Progression: Any patient with disease progression should be removed from study.  
Details and tumor measurements should be documented on flow sheets. 
Considerations about tumor-measurement and disease progression in immunotherapy:  
Because response to immunotherapy involves inflammation of lesions and infiltration by lymphocytes, it 
is common for lesions that are responding to immunotherapy to become physically larger and inflamed 
before tumors begin to shrink in size. In addition small previously occult lesions may become clinically 
detectable once they are inflamed after immunotherapy so the appearance of small new lesions should not 
automatically be considered disease progression without confirmation.  It takes time for a cellular 
immune response to develop after immunotherapy and it’s best to wait 9-12 weeks after immunotherapy 
to begin assessment of potential response. Similarly, apparent tumor progression based on lesion 
measurements should be confirmed by another evaluation (or biopsy if possible) after 3-4 weeks unless 
accompanied by other signs of clinical deterioration.  A biopsy largely devoid of lymphocyte infiltration 
is consistent with tumor progression, whereas the biopsy of a lesion showing extensive lymphocyte 
infiltration may be a sign of inflammation that could lead to subsequent response. 
 
Patient is unable to tolerate the toxicity resulting from the study treatment, even with optimal 
supportive care, in the opinion of the Treating Physician. Adverse event(s) that, in the judgment 
of the investigator, may cause severe or permanent harm or which rule out continuation of study 
drug.  
 
The physician feels it is in the best interest of the patient to stop the treatment. 


3/28/16/pg. 55 
 
 
Inter current illness that would, in the judgment of the Investigator, affect assessment of clinical 
status to a significant degree or require discontinuation of study treatment 
 
Non protocol chemotherapy or immunotherapy is administered during the study 
 
Noncompliance with protocol or treatment—major violation 
 
Suspected Pregnancy 
 
Patient is lost to follow-up 
 
Patient refuses to continue treatment (patient will continue to be followed for disease-free 
survival and overall survival) 
 
Patient request 
 
General or specific changes in the patient’s condition unacceptable for further treatment in the 
judgment of the investigator 
 
Progressive disease at any time 
 
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed.  The primary reason for a patient’s withdrawal from the study is to be recorded in the 
source documents. 
 
Study closure 
 
Death 
 
Subject has major surgery or implanted device that poses a high risks of 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)).  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 
In this event notify: 
Brown University Oncology Research Group (BrUOG) Central Office, 
Phone:  (401) 863-3000, 
Fax:  (401) 863-3820 
Kayla_Rosati@brown.edu 
 
The BrUOG Central Office will in turn notify the Principal Investigator. 
*Document the reason(s) for withdrawal on flow sheets.  Follow the patient for survival with follow-up 
forms as dictated by the protocol 
 
13.0 FOLLOW-UP  
All Subjects that discontinue treatment early for any reason as well as patients who complete therapy will 
be followed for survival. See section 6 for details. At treatment discontinuation, subjects will undergo 
adverse event evaluation and again approximately 30 days post the last dose of study drug (treatment). In 
addition off study evaluations will be done when treatment is discontinued -Section 6.0.Reminder for 
patients who enroll to amendment # 16 or later versions: patients may not and should not receive 
treatment with PI3K or TNFα inhibitors post this study treatment. If a patient is known to receive 
treatment with a PI3K or TNFα inhibitor BrUOG must be made aware via the concomitant medication 
log. Following the completion of the 6 month oral antibiotic treatment, a subject will be eligible to 
participate in other investigational clinical studies.  
 
14.0 REGULATORY CONSIDERATIONS 
14.1 Protection of Human Subjects 
The Investigator must ensure that patients or their legally acceptable representatives are clearly and fully 
informed about the purpose, potential risks and other critical issues regarding clinical trials in which they 
volunteer to participate.  Preparation of the consent form is the responsibility of the Investigator and must 
include all elements required by CFR 21 Part 50.25 and the local IRB. 
 
 


3/28/16/pg. 56 
 
14.2 Compliance with the Protocol and Protocol Revisions: 
The study must be conducted as described in this approved protocol.   
 
All revisions to the protocol must be provided to Brown University Oncology Research Group, and 
Advaxis.  The Investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion from the IRB/IEC and Advaxis of an Amendment, 
except where necessary to eliminate an immediate hazard(s) to study patients. 
 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be sent to 
Brown University Oncology Research Group, and Advaxis.  If the revision is an Administrative Letter, 
Investigators must inform their IRB(s)/IEC(s).  
 
The Investigator must ensure that patients or their legally acceptable representatives are clearly and fully 
informed about the purpose, potential risks and other critical issues regarding clinical trials in which they 
volunteer to participate.  Preparation of the consent form is the responsibility of the Investigator and must 
include all elements required by CFR 21 Part 50.25 and the local IRB. 
 
After the study has been fully explained, written informed consent will be obtained from either the patient 
or his/her guardian or legal representative prior to study participation.  The method of obtaining and 
documenting the informed consent and the contents of the consent will comply with ICH-GCP and all 
applicable regulatory requirement(s). 
 
14.3 Protocol amendments or changes in study conduct:  
Any change or addition (excluding administrative) to this protocol requires a written protocol amendment 
that must be reviewed and approved by Brown University Oncology Research Group, Advaxis and the 
investigator before implementation. Amendments significantly affecting the safety of subjects, the scope 
of the investigation or the scientific quality of the study require additional approval by the IRB at each 
study center.  A copy of the written approval of the IRB must be provided to Brown University Oncology 
Research Group, and Advaxis. 
 
Examples of amendments requiring such approval are: 
 
increases in drug dose or duration of exposure of subjects, 
 
significant changes in the study design (e.g. addition or deletion of a control group), 
 
increases in the number of invasive procedures, 
 
addition or deletions of a test procedure required for monitoring of safety. 
 
These requirements for approval should in no way prevent any immediate action from being taken by the 
investigator or by Brown University Oncology Research Group and Advaxis in the interests of preserving 
the safety of all patients included in the trial.  If an immediate change to the protocol is felt to be 
necessary by the investigator and is implemented for safety reasons Brown University Oncology Research 
Group and Advaxis must be notified and the IRB at the center must be informed immediately. 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB approval but the IRB must be kept informed of such administrative changes.  
Examples of administrative changes not requiring formal protocol amendments and IRB approval include: 
 
changes in the staff used to monitor trials (Advaxis considers a change in Principal Investigator or 
the addition of sub-site(s) to be substantial and requires Advaxis approval prior to 
implementation) 
 
Minor changes in the packaging or labeling of study drug. 
 
 
 


3/28/16/pg. 57 
 
15.0 DATA MONITORING / QUALITY ASSURANCE/ RECORD RETENTION 
15.1 Good Clinical Practice:  
The study will be conducted in accordance with the International Conference on Harmonisation (ICH) for 
Good Clinical Practice (GCP) and in the US Code of Federal Regulations.  The investigator will be 
thoroughly familiar with the appropriate use of the drug as described in the protocol and Investigator’s 
Brochure.  Essential clinical documents will be maintained to demonstrate the validity of the study and 
the integrity of the data collected.  Master files should be established at the beginning of the study, 
maintained for the duration of the study and retained according to the appropriate regulations.   
 
15.2 Patient Confidentiality:  
In order to maintain patient privacy, all data capture records, drug accountability records, study reports 
and communications will identify the patient by initials and the assigned patient number.  The 
investigator will grant monitor(s) and auditor(s) from Advaxis or its designees and regulatory authority 
(ies) access to the patient’s original medical records for verification of data gathered on the data capture 
records and to audit the data collection process.  The patient’s confidentiality will be maintained and will 
not be made publicly available to the extent permitted by the applicable laws and regulations. 
 
15.3 Protocol Compliance:  
The investigator will conduct the study in compliance with the protocol given approval/favorable opinion 
by the IRB/IEC and the appropriate regulatory authority (ies).  Changes to the protocol will require 
approval from Advaxis and written IRB/IEC approval/favorable opinion prior to implementation, except 
when the modification is needed to eliminate an immediate hazard(s) to patients.  The IRB/IEC may 
provide, if applicable regulatory authority (ies) permit, expedited review and approval/favorable opinion 
for minor change(s) in ongoing studies that have the approval /favorable opinion of the IRB/IEC.  The 
investigator will submit all protocol modifications to Advaxis and the regulatory authority (ies) in 
accordance with the governing regulations.  
 
Any departures from the protocol must be fully documented in the source documents.   
 
15.4 On-site Audits:  
Regulatory authorities, the IEC/IRB and/or Advaxis clinical quality assurance group may request access 
to all source documents, data capture records, and other study documentation for on-site audit or 
inspection.  Direct access to these documents must be guaranteed by the investigator, who must provide 
support at all times for these activities. 
 
15.4.1 INSTITUTIONAL AUDITS  
It is the intent that audits will be completed per the BrUOG audit Manual. Audits will be scheduled more 
frequently if required. Auditors will follow procedures established by BrUOG SOP’s. Instructions for 
preparing for the audit will be sent to sites in advance of the audit date. With these instructions, the 
auditors will specify which case records will be reviewed during the audit. Auditors will review on-site 
records against the submitted form, and they will record their findings on specially prepared 
questionnaires. Major discrepancies will be forwarded to the appropriate oversight body within BRUOG 
and the institution. IRB procedures, approvals, and consent forms will also be reviewed at the audit.  
 
To help sites prepare for audits and assure that clinical research associates to maintain records 
appropriately, the BrUOG data management and auditing department will offer training. This training will 
cover all aspects of data collection, but will include special instructions for finding and filing the kinds of 
source documentation needed to verify the accuracy of submitted data for this trial.  
 
15.5 Institutional Review Board:  
Sites must obtain local IRB initial approval. Prior to subject registration, a copy of the IRB approval letter 
for the protocol and the informed consent form must be sent to BrUOG, along a copy of the IRB approved 


3/28/16/pg. 58 
 
informed consent form. Investigator will provide a copy(s) of IRB approval letter(s) for any 
amendment(s), and copy(s) of annual renewal(s). 
 
15.6 Drug Accountability:  
Accountability for the drug at all study sites is the responsibility of the principal investigator.  The 
investigator will ensure that the drug is used only in accordance with this protocol.  Drug accountability 
records indicating the drug’s delivery date to the site (if applicable), inventory at the site (if applicable), 
use by each patient, and return to Advaxis for disposal of the drug (if applicable and if approved by 
Advaxis) will be maintained by the clinical site.  Accountability records will include dates, quantities, lot 
numbers, expiration dates (if applicable), and patient numbers.   
 
15.7 Use and Completion of Case Report Forms (CRF’S) and Additional Request: 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to the 
technology used) designed by the Sponsor to record (according to Sponsor instructions) all observations 
and other data pertinent to the clinical investigation. All CRFs should be completed in their entirety to 
ensure accurate interpretation of data. Should a correction be made, the corrected information will be 
updated with the initials and date of the person modifying the data and initial information. An audit trail 
will allows identifying the modification. Data will be available within the system to the sponsor 
pharmaceutical company as soon as they will be entered in the CRF. 
 
15.9 Source Documents: 
Source data are found in all information, original records of findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents. Source documents represent the first recording of any observations made or data 
generated about a study participant while he or she is enrolled in a clinical trial. Source documents for 
each study participant substantiate the data that are submitted to BrUOG. Source documents must verify 
the eligibility criteria and data submitted on all CRFs. If an item is not mentioned in the source documents 
(e.g., history and physical with no mention of a psychological condition), it will be assumed it is not 
present. Research records for each case should contain copies of the source documents for the data 
reported to BrUOG. If data is abstracted from medical charts that are not filed at the investigative sites 
(e.g. hospital charts), copies of these records should be filed in the research chart. However, every attempt 
must be made to obtain all records/charts that were used to abstract any study data for this protocol at the 
time of the audit visit. This will prevent any discrepancies and the inability to verify the document and the 
data reported.  
 
15.10 Record Retention:  
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).   
 
The Brown University Oncology Research Group, as coordinator of this study, is responsible for ensuring 
proper conduct of the study with regard to protocol adherence and the validity of the data recorded on the 
case report forms. The Principal Investigator (Howard Safran, M.D.) and the Brown University Oncology 
Research Group will monitor this study. Efforts will be made to review the case report forms against the 
submitted documents for accuracy, completeness, adherence to the protocol and regulatory compliance.  
 
U.S. FDA regulations (21CFR312.62[c] require all records and documents pertaining to the conduct of 
this study and the distribution of investigational drug, including CRFs, consents forms, laboratory test 
results and medication inventory records, must be retained by the Principal Investigator for 2 years after 
marketing application approval. If no application is filed, these records must be kept 2 years after the 
investigation is discontinued and the FDA and the applicable local health authorities are notified. Advaxis 
will notify the Principal Investigator if an application is filed.  
 


3/28/16/pg. 59 
 
15.11 Premature Closure of the Study: This study may be prematurely terminated, if in the opinion of 
the investigator or Advaxis, there is sufficient reasonable cause.  Written notification documenting the 
reason for study termination will be provided to the investigator or Advaxis by the terminating party.   
Circumstances that may warrant termination include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to patients 
 
Failure to enter patients at an acceptable rate 
 
Insufficient adherence to protocol requirements 
 
Insufficient complete and/or evaluable data 
 
Plans to modify, suspend or discontinue the development of the drug 
 
16.0 DATA SAFETY AND MONITORING BOARDS 
All trials initiated by the Brown University Oncology-research Group (BrUOG) are subject to oversight 
by the Data Safety Monitoring Board (DSMB).  This board meets two times per year with any additional 
meetings scheduled when needed.  The responsibilities are as follows: 
 
Familiarize themselves with the research protocol (s)  
 
The DSMB reviews trial performance information such as accrual information.   
 
Review interim analyses of outcome data and cumulative toxicity data summaries to determine 
whether the trial should continue as originally designed, should be changed, or should be 
terminated based on these data.   
 
The DSMB also determines whether and to whom outcome results should be released prior to the 
reporting of study results. 
 
All adverse events are reviewed by the committee, with assurances that these have been in fact 
sent for review to all pertinent IRBs. 
 
Review of reports of related studies to determine whether the monitored study needs to be 
changed or terminated. 
 
Review major proposed modifications to the study prior to their implementation (e.g., 
termination, dropping an arm based on toxicity results or other reported trial outcomes, increasing 
target sample size). 
 
Following each DSMB meeting, provide the study leadership with written information concerning 
findings for the trial as a whole related to cumulative toxicities observed and any relevant 
recommendations related to continuing, changing, or terminating the trial.  The study leadership will 
provide information on cumulative toxicities and relevant recommendations to the local principal 
investigators to be shared with their IRB’s. 
 
 
17.0 STATISTICS 
17.1 Primary objective of this phase II study is to assess the clinical complete response at the 6 month 
biopsy. The unacceptable complete response rate is < 50%. The regimen will be considered promising if 
the complete response rate is > 80%. Progression-free and overall survival will be determined from the 
time of study enrollment for all patients that received the study treatment.  
 
Let ‘pR’ be the probability of response to treatment, ‘pT’ the probability of  unacceptable toxicites with 
treatment 
H0: pR ≤ pR0 OR pT ≥ pT0 
       
HA: pR ≥ pR0 AND pT≤  pT0 
 
Simon's two-stage design63 will be used. The null hypothesis that the true response rate is 50% (p0) will 
be tested against a one-sided alternative. In the first stage, 16 patients will be accrued. If there are 10 or 
fewer responses in these 16 patients, the study will be stopped early for futility. Otherwise, 9 additional 
patients will be accrued for a total of 25. The null hypothesis will be rejected if 18 or more responses are 
observed in 25 patients. This design yields a type I error rate of 0.019 and power of 86% when the true 
response rate is 80% (p1).  


3/28/16/pg. 60 
 
 
Toxicities will be recorded by NCI common toxicity version 4.Toxicities will be monitored continuously.  
Unacceptable toxicities will be defined as grade 3 toxicities lasting > 72 hours or grade 4 toxicities of any 
duration, related to ADXS11-001. For toxicity assessment, the target probability of unacceptable 
toxicities is set at 20% for this study (pT0). A rate of grade 3 or grade 4 toxicities related to ADXS11-001 
of >20% is considered a reason to terminate the study and accept the null hypothesis. 
 
An interim analysis for toxicity will be carried out after accruing the first 16 patients. If 3 or more patients 
develop unacceptable toxicities, the study will be stopped early for excess toxicity. If <3patients have 
unacceptable toxicities, the study will continue until 25 patients are accrued. If 5 or more patients 
developed unacceptable toxicities at this stage, the null hypothesis will be accepted and no further 
investigation of the drug is warranted. 
 
Total sample size = 25 treated patients.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


3/28/16/pg. 61 
 
18.0 REFERENCES 
1. Watson M,  Saraiya M, Ahmed F, et al. Using population-based cancer registry data to assess the 
burden of human papillomavirus-associated cancers in the United States: Overview of methods. Cancer 
2008; 113:2841–2854. 
 
2. Nigro ND, Vaitkevicius VK, Considine B Jr., et al. Combined therapy for cancer of the anal canal: a 
preliminary report. Dis Colon Rectum 1974 ; 17:354-356.  
 
3. Bartelink H, Roelofsen F, Eschwege F, et al. Concomitant radiotherapy and chemotherapy is superior 
to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized 
trial of the European Organization for Research and Treatment of Cancer Radiotherapy and 
Gastrointestinal Cooperative Groups. J Clin Oncol 1997; 15:040-2049. 
 
4. Flam M, John M, Pajak TF, et al. Role of mitomycin in combination with fluorouracil and 
radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid 
carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol 1996; 14: 
2527-2539. 
 
5. Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin and radiotherapy vs fluorouracil, 
cisplatin and radiotherapy for carcinoma of the anal canal: A randomised controlled trial. JAMA 2008 ; 
29 :1914-1921. 
 
6. James R, Wan S, Glynne-Jones R, et al. A randomized trial of chemoradiation using mitomycin or 
cisplatin, with or  without maintenance cisplatin/5FU in squamous cell carcinoma of the anus (ACT II). J 
Clin Oncol 2009;27:18s (suppl; abstract LBA4009). 
 
7. Das P, Bhatia S, Eng C, et al. Predictors and patterns of recurrence after definitive chemoradiation for 
anal cancer. Int J Radiat Oncol Biol Phys 2007; 68: 794-800. 
 
8. Gunderson L, Winter K, Ajani J, et al. Long-term Update of RTOG 98-11 Phase III Trial for Anal 
Carcinoma: Concurrent Chemo-radiation With 5-FU Mitomycin vs. 5-FU Cisplatin Improves Disease-
Free and Overall Survival. Presented at: American Society of Clinical Oncology (ASCO) GI Cancer 
Symposium; January 20-22, 2011; San Francisco, CA. J Clin Oncol 2011; 29:(4; Feb 3 suppl): abstract 
367. 
 
9. Frish M, Glimelius B, Van Den Brule AJ, et al. Sexually transmitted infection as a cause of anal 
cancer. N Engl J Med 1997; 337:1350-1358. 
 
10. Tilson P. Anal human papillomavirus and anal cancer. J Clin Path 1997; 50:625-634. 
 
11. Daling JR, Madeleine MM, Johnson LG, et al. Human papillomavirus, smoking and sexual practices 
in the etiology of anal cancer. Cancer 2004; 101:270-280. 
 
12. Gillison M, D'Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus type 
16-positive and human papillomavirus 16-negative head and neck cancers. J Natl Cancer Inst 2008; 100: 
407-420. 
 
13. De Vuyst H, Clifford GM, Nascimento MC, et al. Prevalence and type distribution of human 
papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis. 
Int J Cancer 2009; 124: 1626-1636. 
14. Rampias T, Sasaki C, Weinberger P, et al. E6 and E7 gene silencing and transformed phenotype of 
human papillomavirus 16-positive oropharyngeal cancer cells. J Natl Cancer Inst 2009;101:412-423. 


3/28/16/pg. 62 
 
 
15. Huang CC, Qiu JT, Kashima ML, et al. Generation of type-specific probes for the detection of single-
copy human papillomavirus by a novel in situ hybridization method. Mod Pathol 1998; 11:971-977. 
 
16. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with 
oropharyngeal cancer. N Engl J Med 2010; 363:4-35.  
17. Smith JS, Lindsay L, Hoots B, et al. Human papillomavirus type distribution in invasive cervical 
cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer. Aug 2007;121(3):621-632. 
 
18. Ellis JR, Keating PJ, Baird J, et al. The association of an HPV16 oncogene variant with HLA-B7 has 
implications for vaccine design in cervical cancer. Nat. Med. 1995;1:464-470. 
 
19. Stanley M, Coleman N, Chambers M. The host response to lesions induced by human papillomavirus. 
Ciba Found Symp. 1994;187:21-32. 
 
20. Frankel FR, Hegde S, Lieberman J, Paterson Y. Induction of a cell-mediated immune response to HIV 
gag using Listeria monocytogenes as a live vaccine vector. J Immunol. 1995;155:4766-4774.  
 
21. Einstein MH, Kadish AS, Burk RD, at al. Heat shock fusion protein-based immunotherapy (HspE7) 
for treatment of cervical intraepithelial neoplasia (CIN) III (NCI 5850). Manuscript submitted for 
publication. 2006. 
 
22. Nventa Biopharmaceuticals Corporation (formerly Stressgen). Warts with HPV’s other than type 16 
respond to HspE7 treatment [unpublished, internal document]. San Diego, CA. 
 
23. Davidson EJ, Boswell CM, Sehr P, et al. Immunological and clinical responses in women with vulval 
intraepithelial neoplasia vaccinated with a vaccinia virus encoding human papillomavirus 16/18 
oncoproteins. Cancer Research. 2003;63:6032-6041. 
 
24. Luxton JC, Rowe AJ, Cridland JC, Coletart T, Wilson P, Sheperd P. Proliferative T cell responses to 
human papillomavirus type 16 E7 protein in women with cervical dysplasia and cervical carcinoma and in 
healthy individuals. J G. Virol. 1996;77:1585-1593. 
 
25. Slevy LA, Tindle RW, Geysen HM, Haller C, Smith JA, Frazer IH. Identification of B-epitopes in the 
human papillomavirus 18 E7 open reading frame protein. J Immunol. 1990;145(9):3105-3110. 
 
26. Krchnak V, Vagner J, Suchankova A, Kremar M, Ritterova LO, Vonka V. Synthetic peptides derived 
from E7 region of human papillomavirus type 16 used as antigens in ELISA. J Gen Virol. 1990;71:2719-
2724. 
 
27. McCarthy C, Youde SJ, Man S. Definition of an HPV-18/45 cross reactive human T-cell epitope after 
DNA immunization of HLA-A2/KB transgenic mice. Int J Cancer. 2005;118(10):2514-2521. 
 
28. Nilges K, Hohn H, Pilch H, et al. Human papillomavirus tyupe 17 E peptgide-directed CD8+ T cells 
from patients with cervical cancer are cross-reactive with the cornavirus NS2 protein. J Virol. 
2003;77(9):5464-5467. 
 
29. Sanda MG, Restifo NP, Walsh JC, et al: Molecular characterization of defective antigen processing in 
human prostate cancer. J Natl Cancer Inst 87:280-285, 1995 
 
30. Apetoh L, Ghiringhelli F, Tesniere A, et al: Toll-like receptor 4-dependent contribution of the 
immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050-1059, 2007 
 


3/28/16/pg. 63 
 
31. Chakraborty M, Abrams SI et al (2003) Irradiation of tumor cells up-regulates Fas and enhances CTL 
lytic activity and CTL adoptive immunotherapy. J Immunol 170:6338–6347 
 
32. Reits EA, Hodge JW et al (2006) Radiation modulates the peptide repertoire, enhances MHC class I 
expression, and induces successful antitumor immunotherapy. J Exp Med 203:1259–1271 
 
33. Obeid M, Tesniere A et al (2007) Calreticulin exposure dictates the immunogenicity of cancer cell 
death. Nat Med 13:54–61 
 
34. Younes E, Haas GP, Dezso B, et al: Local tumor irradiation augments the response to IL-2 therapy in 
a murine renal adenocarcinoma. Cell Immunol 165:243-251, 1995 
 
35. Chakraborty M, Abrams SI, Coleman CN, et al: External beam radiation of tumors alters phenotype of 
tumor cells to render them susceptible to vaccine mediated T-cell killing. Cancer Res 64:4328-4337, 2004 
 
36. Chi KH, Liu SJ et al (2005) Combination of conformal radiotherapy and intratumoral injection of 
adoptive dendritic cell immunotherapy in refractory hepatoma. J Immunother 28:129–135 
 
37. Okawa T, Kita M et al (1989) Phase II randomized clinical trial of LC9018 concurrently used with 
radiation in the treatment of carcinoma of the uterine cervix. Its effect on tumor reduction and histology. 
Cancer 64:1769–1776 
 
38. Gulley JL, Arlen PM et al (2005) Combining a recombinant cancer vaccine with standard definitive 
radiotherapy in patients with localized prostate cancer. Clin Cancer Res 11:3353–3362 
 
39. Phase I trial of ipilimumab (IPI) alone and in combination with radiotherapy (XRT) in patients with 
metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol 26: 2008 (May 20 suppl; abstr 
5004) 
 
40. Slovin SF, Beer TM, Higano CS, et al: Initial phase II experience of ipilimumab (IPI) alone and in 
combination with radiotherapy (XRT) in patients with metastatic castration-resistant prostate cancer 
(mCRPC). J Clin Oncol 27:268s, 2009 (suppl; abstr 5138) 
 
41. Pan Z-K, Ikonomidis G, Pardoll D, Paterson Y. Regression of established tumors in mice mediated by 
the oral administration of a recombinant Listeria monocytogenes vaccine. Cancer Research. 
1995;55:4776-4779. 
 
42. Wallecha A, Carroll KD, Maciag PC, Rivera S, Shahabi S, Paterson Y. Multiple effector mechanisms 
induced by recombinant Listeria monocytogenes anti-cancer immunotherapeutics. Advances in 
Microbiology [In press]. 2009;66. 
 
43. Hussain SF, Paterson Y. CD4+ CD25+ regulatory T ce3lls that secrete TFGβ and IL-10 are 
preferentially induced by a vaccine vector. J Immunother. 2004;27(5):339-46. 
 
44. Shahabi V, Reyes-Reyes M, Wallecha A, Riveria S, Paterson Y, Maciag PC. Development of a 
Listeria monocytogenes based vaccine against prostate cancer. Cancer Immunol Immunother. 
2008;57:1301-13. 
 
45. Tindle RW. Human papillomavirus vaccines for cervical cancer. Curr. Opin. Immunol. 1996;8:643-
650. 
 
46. Slifka MK. The future of smallpox vaccination: is MVA the key? Med Immunol. 2005;1:2. 
 


3/28/16/pg. 64 
 
47. Raper SE, Chirmule N, Lee FS, et al. Fatal systemic inflammatory response syndrome in a ornithine 
transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab. 2003;80:148-
158. 
 
48. Paterson Y, Johnson RS. Progress towards the use of Listeria monocytogenes as a live bacterial 
vaccine vector for the delivery of HIV antigens. Expert Review of Vaccines. (AIDS vaccines supplement) 
Ed. E. Emmini and D. Weiner 2004;3:119-134. 
 
49. Jacobson NG, Szabo SJ, Guler ML, Gorham JD, Murphy KM. Regulation of interleukin-12 signalling 
during T helper phenotype development. Adv Exp Med Biol.1996;409:61-73. 
 
50. Jacobson NG, Szabo SJ, Guler ML, Gorham JD, Murphy KM. Regulation of interleukin-12 signaling 
during T helper phenotype development. Adv Exp Med Biol.1996;409:61-73. 
 
51. Gunn GR, Zubair A, Peters CH, Pan Z-K, Wu T-C, Paterson, Y. Two L. monocytogenes vaccine 
vectors that express different molecular forms of HPV-16 E7 induce qualitatively different T cell 
immunity that correlates with their ability to induce regression of established tumors immortalized by 
HPV-16. J Immunol. 2001;167:6471-6479. 
 
52. Cheers C, McKenzie IF, Pavlov H, Waid C, York J. Resistance and susceptibility of mice to bacterial 
infection: course of listeriosis in resistant or susceptible mice. Infection and Immunity. 1978;19:763-770.  
 
53. Quesada A. Acute Dose Toxicity of Lm-LLO-E7 in Babl/C Mice. GLP Study # 8920-05. 
Stillmeadow, Inc. 2005;Sugar Land, TX. 
 
54. Quesada A. Four week study of Lm-LLO-E7 vector Mice. GLP Study # 8985-05. Stillmeadow, Inc. 
2005;Sugar Land, TX. 
 
55. Quesada A. Acute Intravenous Toxicity Study of Lm-LLO-E7 in Female SCID Mice. GLP Study # 
9190-05. Stillmeadow Inc. 2005;Sugar Land, TX. 
 
56. Quesada A. Biodistribution Study of Lm-LLO-E7 in Female Mice. GLP Study # 8986-05. 
Stillmeadow Inc. 2005;Sugar Land, TX. 
 
57. Quesada A. Acute Intravenous Clearance Study of Lm-LLO-E7 in Female Mice. GLP Study # 9189-
05. Stillmeadow Inc. 2005;Sugar Land, TX. 
 
58. Quesada A. 2005. Clearance Study of Intravenous Administration of Lm-LLO-E7 in Female Balb/C 
Mice. GLP Study # 9355-05. Stillmeadow Inc. 2005;Sugar Land, TX. 
 
59. Schafer R, Portnoy DA, Brassell SA, Paterson Y. Induction of a cellular immune response to a foreign 
antigen by a recombinant Listeria monocytogenes vaccine. J Immunol. 1992;149:53-59. 
 
60. Macig, PC, Radulovic, S. and Rothman J.  The first clinical use of a live-attenuated Listeria 
monocytogenes vaccine: A Phase I safety study of Lm-LLO-E7 in patients with advanced carcinoma of 
the cervix   Vaccine (2009) 27;3975–3983 
 
61. Petit RG, Aqua KA, Basu P, et al. ADXS11-001 immunotherapy: Preliminary safety data from two P2 
studies in women with CIN 2/3 and with recurrent/refractory cervical cancer. From Poster presentation, 
ASCO 2012, J  Clin Oncol 30, 2012 (suppl; abstr e15546). 
 
62. Glynne-Jones R, James R, Meadows H, et al. Optimum time to assess complete clinical response (CR) 
following chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP) with or without 


3/28/16/pg. 65 
 
maintenance CisP/5-FU in squamous cell carcinoma of the anus. Results of ACT II. Proc Am Soc Clin 
Oncol 2012, abstr 4004. 
 
63. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989. Mar 
;10(1):1-10. 
64. Tocilizumab, Package Insert. Genentech, Inc., 2014. 
65. Grupp, S.A., et al., Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J 
Med, 2013. 368(16): p. 1509-18. 
66. Winkler, U., et al., Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia 
and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-
C2B8). Blood, 1999. 94(7): p. 2217-24. 
 
67. Lee, D.W., et al., Current concepts in the diagnosis and management of cytokine release syndrome. 
Blood, 2014. 124(2): p. 188-95. 
 
68. http://www.cdc.gov/listeria accessed September 23, 2015 
 
69. Beebe, J.L. and E.W. Koneman, Recovery of uncommon bacteria from blood: association with 
neoplastic disease. Clin Microbiol Rev, 1995. 8(3): p. 336-56. 
 
70. Le Monnier, A., et al., Listeria monocytogenes: a rare complication of ventriculoperitoneal shunt in 
children. J Clin Microbiol, 2011. 49(11): p. 3924-7. 
 
71. 
Dominguez, E.A., A.A. Patil, and W.M. Johnson, Ventriculoperitoneal shunt infection due to 
Listeria monocytogenes. Clin Infect Dis, 1994. 19(1): p. 223-4. 
 
72. 
Winslow, D.L. and M.L. Steele, Listeria bacteremia and peritonitis associated with a 
peritoneovenous shunt: successful treatment with sulfamethoxazole and trimethoprim. J Infect Dis, 1984. 
149(5): p. 820. 
 
73. 
Charlier, C., et al., Listeria monocytogenes-associated joint and bone infections: a study of 43 
consecutive cases. Clin Infect Dis, 2012. 54(2): p. 240-8. 
 
74. Chosewood LC, W.D., editors, Biosafety in microbiological and biomedical laboratories (BMBL) 5th 
ed. US Department of Health and Human Services. 
 
75. Davidson, E.J., et al., Immunological and clinical responses in women with vulval intraepithelial 
neoplasia vaccinated with a vaccinia virus encoding human papillomavirus 16/18 oncoproteins. Cancer 
Res, 2003. 63(18): p. 6032-41. 
 
76. Lacey, C.J., et al., Phase IIa safety and immunogenicity of a therapeutic vaccine, TA-GW, in persons 
with genital warts. J Infect Dis, 1999. 179(3): p. 612-8. 


3/28/16/pg. 66 
 
APPENDIX A  
 
Suggested INFORMED CONSENT 
Agreement to Participate in a Research Study 
And Authorization for Use and Disclosure of Information 
 
A Phase I/II Evaluation of ADXS11-001, Mitomycin, 
5-fluorouracil (5-FU) and IMRT for Anal Cancer BrUOG 276 
 
 
You are being asked to take part in a research study.  All research studies carried out at _____ institutions 
are covered by rules of the Federal government as well as rules of the State and _________ institutions.  
Under these rules, the researcher will first explain the study, and then he or she will ask you to participate.  
You will be asked to sign this agreement that states that the study has been explained, that your questions 
have been answered, and that you agree to participate. 
 
The researcher will explain the purpose of the study. He or she will explain how the study will be carried 
out and what you will be expected to do.  The researcher will also explain the possible risks and possible 
benefits of being in the study.  You should ask the researcher any questions you have about any of these 
things before you decide whether you wish to take part in the study.  This process is called informed 
consent. 
 
This form also explains the research study.  Please read the form and talk to the researcher about any 
questions you may have.  Then, if you decide to be in the study, please sign and date this form in front of 
the person who explained the study to you. You will be given a copy of this form to keep. 
 
Nature and Purpose of the Study      
Your doctors are participating in this research study sponsored by the Principal Investigator, Dr. Howard 
Safran, in collaboration with Brown University Oncology Research Group (BrUOG), which will serve as 
the central coordinating office for the study. This study is supported by Advaxis (the makers of ADXS11-
001). 
 
You have been diagnosed with anal cancer. The standard treatment for anal cancer is to use a combination 
of chemotherapy and radiation treatments over approximately 6 weeks. This study will test the addition of 
an experimental drug called ADXS11-001 to standard chemotherapy and radiation for the treatment of 
anal cancer.  
 
The main purpose of this study is to evaluate the safety and effectiveness of ADXS11-001 when 
combined with standard chemotherapy and radiation treatment for anal cancer. ADXS11-001 is an 
investigational agent that is not approved by the FDA to treat anal cancer or any other cancer.    
 
About 25 patients will take part in this study in about 5-7 cancer centers across the United States. 
 
How Does ADXS11-001 Work? 
 
One of the most important risk factors for the development of anal cancer is the presence of the Human 
Papilloma Virus (HPV). A part of a protein made by HPV called HPV E7 can be found inside almost all 
anal cancer cells. ADXS11-001 is an investigational drug that tries to stimulate your body’s immune 
system to attack cancer cells that contain HPV E7. As of September 2015, approximately 675 doses of 
ADXS11-001 have been given to 263 patients with HPV associated cancers. 
 
ADXS11-001 is a modified and weakened version of a bacteria called Listeria monocytogenes.  


3/28/16/pg. 67 
 
The experimental product ADXS11-001 uses a live strain of the Listeria monocytogenes (Lm) bacteria 
that has been genetically modified such that the risk of getting an infection is significantly reduced.  
Inside the Listeria bacteria has been placed part of the molecule for HPV E7. This modified listeria 
bacteria (ADXS11-001), is injected into a patient’s bloodstream. ADXS11-001 then goes inside a 
patient’s lymphocytes which are blood cells of the immune system. This stimulates other immune system 
cells to attack cells that contain HPV E7 including anal cancer cells.  
Explanation of Procedures   
What will happen if I take part in this research study?  
 
Before you begin the study, you will need to have the following exams, tests or procedures to find out if 
you can be in the study.  These exams, tests, or procedures are part of regular cancer care and may be 
done even if you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to the study doctor. 
 
A physical examination and an examination of your anus and groin 
 
Examination and measurement of the cancer using a tube with a light on it (a “scope”) in 
order to see the cancer better; sometimes you will be given a short general anesthetic for 
this examination. 
 
A specimen of the cancer (biopsy) will be removed to examine.  If the study doctor 
suspects cancer in the lymph nodes in the groin, a biopsy may be taken from there too. 
 
An x-ray or a CT scan (a computerized x-ray that gives your doctor clearer pictures of 
the inside of your body) of your chest to make sure your lungs are clear. 
 
A CT scan or an MRI (a test that uses magnets to take pictures of the inside of your 
body) of your abdomen and pelvis to check for any spread of the cancer.   
 
Blood tests to check your bone marrow, kidneys, and liver. 
 
For women able to have children, a pregnancy test because the treatments in this study 
could harm an unborn baby. 
 
An HIV test. If you are HIV positive you will not be eligible for this study because of 
increased chance of side effects. If your HIV test comes back as positive, you will be 
referred to a specialist in HIV treatment. You will still be able to get standard treatment 
for anal cancer but you will not be able to be part of the study and you will not be able to 
receive ADXS11-001.  
 
If you have a previous history of heart disease, your heart strength will be evaluated by 
an ultrasound of your heart called a cardiac echo to see if your heart function is adequate 
to participate in this study.  
 
If you have a previous history of lung disease, your lung function will be evaluated by 
breathing into a machine that measures your lung strength (PFTs) to see if your lung 
function is adequate to participate in this study. 
 
You will be asked about your current health, medical history, surgical history, and the 
medicines that you have taken within 30 days of study entry or are currently taking. The 
study doctor may ask you specifically about medicines called Phosphoinositide 3-kinase 
inhibitors (PI3K, such as idelalisib (Zydelig)) and Tumor Necrosis Factor (TNF, such as 
humira (adalimumab), enbrel (etanercept)) alpha inhibitors. These medicines might 
interact with ADXS011-001 to cause adverse effects. You cannot be on one of these 
medicines to enter the study, take one during your participation in the study or after your 
participation in the study is completed.    
 
You will be asked if you have received any live vaccines within the past 30 days as this 
may affect your study participation.  Examples of live vaccines include, but are not 
limited to:  measles, mumps, rubella, chicken pox, yellow fever, rabies, 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 
not allowed within 30 days. Please speak with your study doctor about any vaccines you 
have recently received. 


3/28/16/pg. 68 
 
 
Treatments: 
If you are determined to be eligible for the study, and you consent to be part of the study, you will receive 
standard radiation and chemotherapy for anal cancer. You will also receive ADXS11-001.  
 
Standard Radiation Therapy and Chemotherapy (Mitomycin and 5-FU) For Anal Cancer:  
Radiation: 
You will receive radiation once a day, five days a week, for 30 treatments (6 weeks) depending on your 
cancer.   
 
Sometimes you may need a break (usually a week but it may be longer depending on your case) in the 
radiation treatment due to the side effects from the radiation, such as vomiting, diarrhea, skin rash, or 
lowered blood counts. The study doctor will be checking your side effects throughout treatment. 
 
 
Chemotherapy: 
You will receive two drugs: Mitomycin and 5-fluorouracil (5-FU) in two treatments. The first 
chemotherapy treatment starts on the same day as your first radiation treatment (day 1).  The second 
treatment is given at the start of the fifth week of radiation (approximately day 29). The mitomycin is 
given through your vein over about 15 minutes. The 5-FU also is given through your vein, but it has to be 
given continuously over 96 hours (starting on day 1 and approximately again on day 29). Typically, if you 
start radiation on a Monday, your 5-FU will be started that day and be stopped on Friday.  This means 
that although the 5-FU is given for 96 hours, you will receive some 5-FU on each of 5 days (Monday to 
Friday). 
 
Treatment with ADXS11-001 
 
You will receive 4 treatments with ADXS11-001 as a 60-minute infusion through the vein.  Your first 
treatment will be 6-14 days before your first radiation. The second treatment of ADXS11-001 will be 
given approximately 10 days - 28 days after completion of radiation. The third treatment will be given 
approximately 28 days after the second treatment and the fourth treatment will be approximately 28 days 
later.  
 
 
Administration of drug: You will have a new infusion line place for each infusion of 
ADXS11-001. Central venous catheters or infusion ports that you currently have or that you 
recently had placed are not allowed to be used for ADXS11-001 administration.  
 
Patients with central venous catheters or infusion ports: If you currently have or will have a 
central venous catheter or infusion port placed, it is important you understand that the 
catheters or port must not be used for 72 hours following the completion of the ADXS11-
001 infusion and not until after you take your first dose of antibiotics. This is required with 
each of the 4 infusions of ADXS11-001. 
 
Medications prior to ADXS11-001: You will be asked to take an oral medication to control 
any possible nausea or vomiting related to the infusion, such as promethazine, ondansetron, 
or prochlorperazine. You will also receive an acid reducer (medicines used to reduce 
amount of acid in stomach such as famotidine), and an antihistamine (medicines used 
in treatment of allergies such as diphenhydramine) approximately 30 minutes before 
you receive the study drug.  
 
Naproxen to prevent fever and body aches from ADXS11-001: One day prior and on the 
day of your infusion with ADXS11-001 you will take naproxen, which is a non-steroidal anti-
inflammatory drug that is available over the counter.  Naproxen is being used to try to help 
prevent fever, aches and pains that you may get from taking the ADXS11-001. On the day of 
your infusion, you will be asked to take your Naproxen dose prior to arrival to the study site 


3/28/16/pg. 69 
 
and the evening dose at home (to be taken 8-12 hours after morning dose). For further 
information on naproxen please speak with your study doctor.   
 
 
Clinic Observation after ADXS11-001: You will be observed at the study site for 
approximately 4 hours to make sure there are no unanticipated side effects from the infusion. 
You will need to come back to clinic 24 hours after your infusion and again 72 hours after the 
infusion so that the study team can document your vital signs. 
 
Antibiotics to prevent infection from ADXS11-001: Three days after your infusion 
ofADXS11-001 you will be given either a seven (7) day course of an oral antibiotic called 
Bactrim® (Trimethoprim and Sulfamethoxazole). Depending on the strength of the antibiotic 
your doctor prescribes you will either take the antibiotic  once a day for 7 days (daily) or you 
will take it three (3) times over the 7 days. Your doctor or the research team will explain how 
often you are required to take the antibiotics. .  If you know you are allergic to  Bactrim®, you 
will be given ampicillin in its place, which you will take four times a day for seven days. 
Please ensure that you complete the entire course of antibiotics as prescribed by your 
physician.  The reason for the antibiotic being given is as a precaution to try to ensure that all 
of the Listeria has been eliminated from your body.  If you develop persistent fever within the 
72-hour window between your receiving ADXS11-001 and starting the antibiotic, you will be 
given the 7-day course of antibiotic by vein instead of by mouth.  Your doctor may decide to 
reduce the dose of antibiotic or change to a different antibiotic based on your medical 
condition.  
 
Drug Interactions with ADXS11-001: While you are on this study you should not take any 
immunosuppressive steroids, such as prednisone and prednisolone. Your doctor will review 
all of the medications and supplements you are currently taking before starting you on this 
drug.   You may need to change one or more of your regular medications under the direction 
of your doctor if it is safe to do so in order to participate in this study.  You should not take 
any new medications or dietary supplements without discussing it with your study doctor 
first. It is important that you know you cannot receive any live vaccines within 30 days prior 
to the first dose of ADXS11-001 and while on receiving ADXS11-001. This includes but is 
not limited to: measles, mumps, rubella, chicken pox, yellow fever, rabies, intranasal 
influenza (eg: Flu-mist). The seasonal influenza vaccine for injection is generally a non-live 
virus vaccine and this is allowed. 
 
Devices or surgery: If during the study you need to undergo any surgery during which you 
will have a medical device (such as a prosthetic joint, artificial heart valve, pacemaker, 
orthopedic screw, bone graft, or other implant) implanted you will be need to be taken off the 
study secondary to the small, but potential risk of delayed listeria. 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.   
 
Additional Precautions after treatment with ADXS11-001:  There may be a live bacterium 
in your body for a few days after your treatment. The ampicillin is given after 3 days to try to 
eliminate the bacteria.  The bacteria can, under certain circumstances, be contained in your 
bodily fluid. Healthy people around you are not at risk of getting sick from this bacteria from 
you.  However, it could be transferred to a baby if you are pregnant or through breast milk if 
you are nursing. This is why women who are pregnant or nursing cannot participate in the 
trial.  As a precaution, you should not exchange bodily fluids with someone who has a 
weakened immune system (for example, persons with leukemia, lymphoma, AIDS, or a 
positive blood test for HIV) during the time between when you receive the infusion until 3 
days after you start the antibiotics.  In clinical studies, the bacteria are cleared from the 
bloodstream quickly with no evidence of the bacteria being present in the urine or feces of 
any patient. ADXS11-001 has been administered over 500 times to patients. There have been 
no instances of person-to-person transmission.  


3/28/16/pg. 70 
 
 
Lm Surveillance Monitoring: After study treatment is completed, you will be monitored for 
3 years for a possible delayed listeria infection. During the first 6 months of your 
participation in this period you will receive a daily dose of oral Bactrim which is an antibiotic 
used to treat an infection from listeria. The goal of receiving this treatment is that the Bactrim 
will kill any listeria that might still be in your body from the ADXS11-001 treatment. In 
addition, you will have routine blood tests and cultures which will require about 5 teaspoons 
of blood.  These will be obtained approximately every 4 months for 3 years. The first blood 
test and culture will be obtained approximately 4 months after you receive your first dose of 
Bactrim. If you are allergic to or cannot tolerate Bactrim or develop a hypersensitivity to it 
during your participation in the study you may receive Ampicillin. This is another antibiotic 
which is used to treat an infection from listeria and kill it in the body. The study doctor will 
be able to help you decide which antibiotic is the one you will receive.       
 
Other treatments: You will be able to participate in other clinical trials only following the 
completion of the 6 month oral antibiotic treatment,. 
 
Tests You Will Need Weekly For 6 Weeks While You Are Receiving Chemotherapy and Radiation: 
During the study treatment you will need the following tests and treatments.  They are part of regular 
cancer care: 
 
Weekly physical examination to check for side effects 
 
Weekly examination of your anus and groin 
 
Weekly blood tests to check for side effects 
 
Follow up: 
You will be seen 1 to 2 weeks after the completion of radiation, then 2-6 weeks after completing 
treatment with ADXS11-001. Following the completion of your study treatment, there will be a 3-year 
follow-up and surveillance period which will include a study visit approximately every 4 months. After 3 
years you will be followed once a year for 2 years (year 4 and year 5). Your participation in this study 
could be a maximum of 6years. In follow-up, you will need the following tests and examinations: 
 
A physical examination 
 
An examination of your anus and groin 
 
Blood tests 
 
A CT scan or an MRI of your abdomen and pelvis 
 
A chest x-ray 
 
An examination of the area of the cancer using a tube with a light on it (a “scope”) 
 
You will be monitored for 5 years after your study treatment is completed. You will be given an oral 
antibiotic for 6 months at the start of this monitoring period. You will have blood tests approximately 
every 4 months during this period for 3 years. The reason for this monitoring is to check to see if any Lm 
bacteria can be found in your blood after receiving treatment with ADXS11-001 which uses Lm bacteria. 
This is called a delayed listeria infection. After 3 years, you will be seen once a year for 2 years (year 4 
and year 5).  
Biopsy of the Anal Cancer: 
Approximately 6 months after you started treatment with radiation and chemotherapy you will have a 
“scope” of your anus and you may have a biopsy. This “scope” is part of standard treatment for anal 
cancer. Your doctor may recommend additional evaluations and biopsies as part of standard follow-up if 
your doctor thinks this is helpful.  
 


3/28/16/pg. 71 
 
If your cancer is still present at the completion of treatment or recurs in the anus, your doctor may 
recommend surgery to remove the anus and rectum. 
 
How long will I be in the study?  
The period from the first treatment of ADXS11-001 which is given 6-14 days prior to starting radiation 
and chemotherapy to the final treatment of ADXS11-001 (which is given after completion of 
chemotherapy and radiation), to the post-treatment scope and biopsy (biopsy only if applicable) is 
approximately 6 months. Afterwards you will be followed every 6 months for 1 year and every year for 
an additional 4 years, to make sure that there are no delayed side effects and that any side effects that did 
happen during the study have improved. 
 
It is important that we know what happens to you over a long-term period of time, so you will be 
followed for 5 years after your study treatment. Also, it is very important that any time you have medical 
problems, medical procedures or surgery that you inform your study doctor.  
 
Can I stop being in the study?  
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping or 
decide to stop.  He or she will tell you how to stop safely If you decide to stop immediately after receiving 
treatment with ADXS11-001, or before completion of the following course of antibiotics, it is critically 
important that you complete the entire course of antibiotics to make sure none of the ADXS11-001 
bacteria remain.   
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
discontinuation of radiation, or chemotherapy can be evaluated by your doctor.  Another reason to tell 
your doctor that you are thinking about stopping is to discuss what follow-up care and testing could be 
most helpful for you.  
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in your 
best interest; if you do not follow the study rules; or if the study is stopped.  
 
Costs for participating in this study  
The investigational drug, ADXS11-001, will be provided at no cost to you by Advaxis.  
Other services you will receive during this research study are considered "routine clinical services" that 
you would have received even if you were not in the research study. These “routine clinical services” 
include the administration of ADXS11-001, pre-medications, all study doctor visits, chemotherapy, blood 
tests, CT scans, PFTs, echocardiogram, HIV test, pregnancy test, the scope at 6 and 12 months after last 
treatment with study drug and then yearly, the post-treatment biopsy at approximately 6 months, radiation 
treatments and MRI scans. These services will be billed to your health insurance company, but you will 
be responsible for paying any deductibles, co-payments, or co-insurance that are a normal part of your 
health insurance plan.  If you do not have health insurance, you will be responsible for those costs.  
 
Contact Information: If you have any questions regarding this study, you may contact your sites  Principal 
Investigator, <INSERT NAME>, MD at <INSERT PHONE NUMBER>. 
Discomforts and Risks 
You may have side effects while on this study.  We will monitor everyone in the study for any side 
effects. Contact your study doctor if you experience a side effect or have any questions about possible 
side effects. 
 
Side effects may be mild or serious.  We may give you medicines to help lessen side effects.  Some side 
effects will go away as soon as you stop taking the drug.  In some cases, side effects can be serious, long-


3/28/16/pg. 72 
 
lasting, or may never go away. 
 
Risks and side effects related to the Radiation Therapy include those which are: 
Likely (more than 10%) 
 
Redness and skin irritation in the treatment area that may result in bleeding and/or infection, 
which may require hospitalization 
 
Loss of pubic hair in the treated area, usually temporary 
 
Tiredness 
 
Nausea and/or vomiting 
 
Sterility (inability to bear children) in fertile women 
 
Sterility (inability to produce children) in men 
Less Likely  (3-9%) 
 
Diarrhea 
 
Sores and bleeding from the bowel (these side effects may occur well after treatment and be 
serious enough to require surgery) 
 
Narrowing and dryness of the vagina (birth canal) and genital area with painful or difficult 
intercourse and possibly bleeding 
 
Development of extra tissue (fibrosis) in the anal canal, which may result in decreased function 
 
Long-term dryness of the skin 
 
Inability to have or keep an erection (impotency) 
 
Hip fracture 
 
Build up of fluid in ankles, feet, and/or legs 
Rare, but serious (less than 2%) 
 
Narrowing or blockage of the bowel (these side effects may occur well after treatment and be 
serious enough to require surgery) 
 
Blockage of the urinary tubes 
 
Development of an abnormal path or connection between organs (fistulae) 
 
Skin damage (tissue death), which may result in surgery 
 
Narrowing of or persistent bleeding in the vagina (birth canal), which may result in surgery  
 
Risks and side effects related to the Chemotherapy (5-FU and Mitomycin) include those which are: 
Likely (more than 10%) 
 
Diarrhea with cramping or bleeding 
 
Nausea and or vomiting 
 
Change in taste, particularly a metallic taste 
 
Loss of appetite 
 
Dry skin with rash, cracking, and/or peeling 
 
Mouth sores and sore throat 
 
Temporary thinning or loss of hair 
 
Low white blood cell count, which may increase the risk of infection 
 
Low red blood cell count, which may result in anemia, tiredness, and/or shortness of breath 
 
Low platelet count, which may result in increased bruising and bleeding 
Less Likely (3-9%)  
 
Eye irritation, watery eyes, and/or runny nose 
 
A blocked tear duct, which may require treatment 
 
Blurred vision 
 
Darkening and thinning of the skin 
 
Darkening, dryness, and marking of the nails 
 
Increased sensitivity to sunlight 
 
Headaches, which may continue 


3/28/16/pg. 73 
 
 
Light-headedness 
 
Fever 
 
Puffiness of the hands and feet 
 
For women, missed menstrual periods 
 
Redness, tenderness, peeling, and/or tingling of the palms and soles of the feet 
 
 
Rare, but serious (less than 2%) 
 
Confusion 
 
Unsteadiness, loss of coordination  
 
Temporary loss of consciousness 
 
Slurred speech 
 
Dry cough and shortness of breath 
 
Tissue damage from leakage of mitomycin from a vein, which may require surgery 
 
Vomiting blood from the digestive tract 
 
Serious infection, which may be life threatening 
 
Irritation of a vein due to a blood clot, which may result in tenderness over the vein and pain in 
the part of the body affected and which may require treatment 
 
Allergic reactions, which can involve flushing, difficulty breathing, and low blood pressure and 
which can be life threatening 
 
Change in heart rhythm 
 
Damage to the heart or spasm of the heart’s blood vessels that can cause chest pain 
 
Heart attack 
 
Kidney damage 
 
Inflammation of the liver, which may result in yellowing of the skin and eyes, tiredness, and/or 
pain on the upper right of the stomach area 
 
Risks and side effects related to the ADXS11-001 include those which are:  
Wild-type Listeria monocytogenes (Listeria) is a naturally occurring bacteria that is present in the 
environment and is known to cause illness in some people when they eat foods contaminated with 
Listeria (such as deli meats and hot dogs, unpasteurized [raw] milk and soft cheeses, uncooked 
vegetables [such as lettuce or celery] and fruits [such as cantaloupe]). ADXS11-001 is a Listeria that has 
been genetically altered in the laboratory so that its ability to cause sickness and infection is reduced. 
Wild type Listeria does not usually cause disease, and most people who encounter it clear the infection 
without even knowing that they have been exposed.  However in some instances Listeria exposure can 
result in an infection with fever, chills or muscle aches or sickness to your gastrointestinal tract (such as 
nausea or diarrhea) or nervous system.  Both wild type Listeria and ADXS11-001 are sensitive to 
antibiotics and are killed after treatment with antibiotic therapy.  However in rare instances Listeria and 
ADXS11-001 can remain in the body even after antibiotic treatment. 
So far, as of September 2015, over 675 doses of ADXS11-001 have been given to over 263 subjects with 
HPV associated cancers in 9 research studies with ADXS11-001 alone or in combination with 
chemotherapy. 


3/28/16/pg. 74 
 
From the clinical experience, the most common side effects associated with ADXS11-001 treatment were 
mainly individual flu-like symptoms and/or cytokine release symptoms.   The symptoms usually start 
within 2-4 hours after the completion of an ADXS11-001 dose, are often mild to moderate in nature, short 
lived, and respond quickly to symptomatic treatment.  In rare instances severe or life-
threatening/disabling side effects that last up to 24 hours have been observed, such as moderate to severe 
low blood pressure.  
Flu-like and/or cytokine release symptoms: a group of symptoms resulting from a substance (cytokines) 
secreted by cells of the immune system which causes an increase in the number of a specific immune 
blood cells, called T-cells.  
Symptoms related to cytokine release may include symptoms that affect the whole body such as fever, 
chills, shaking, feeling physically and mentally exhausted, headache, nausea, vomiting, rash, rapid 
heartbeat, low blood pressure, and shortness of breath which usually occur within 2-4 hours after the 
completion of an ADXS11-001 dose and may last up to 24 hours.    The symptoms are caused by an 
increase in cytokines which have been shown to occur after ADXS11-001 administration, resulting from 
the body’s immune response to the therapy. 
On rare occasions, these side effects may be severe enough to require hospitalization and/or urgent 
treatment.  In these cases, your study doctor may choose to treat these side effects by giving you 
additional fluids, high dose vasopressors (to increase your blood pressure), tocilizumab, corticosteroids, 
or other treatments not listed here.  The study doctor will determine the best treatment needed based on 
the severity of your symptoms. 
Risk of Delayed/Late Listeria Infection:  
Listeremia is the appearance of the strain of Listeria bacteria used in the investigational product 
ADXS11-001 in the blood. It is detected by taking a sample of your blood and testing it. In rare 
circumstances, Listeria bacteria may appear in the blood many weeks to years after receiving a dose of 
ADXS11-001. This is called delayed or late listeria infection.  There was one recently reported case of 
delayed listeria infection from a subject with metastatic cervical cancer who participated in a clinical 
research study. It occurred approximately 2.5 years after the subject received a dose of ADXS11-001. In 
this case, the subject had an artificial body part and received an investigational treatment (PI3K inhibitor) 
for her cancer after completing the study. It is believed that people who have an implanted medical 
device, an artificial body part or bone graft may have a higher risk for getting a delayed Listeria blood 
infection.   In most cases of delayed listeria infection, common symptoms such as a fever, chills, nausea 
and/or diarrhea may be present. A fever was the only symptom associated with a Listeria infection that 
this subject showed. Treatment with an antibiotic may be able to get rid of Listeria symptoms and also kill 
it in the blood.  This subject received treatment with an antibiotic in the hospital which took care of her 
fever and she was able to go home. The subject died about 2 weeks after going home from progression of 
her cervical cancer according to her study doctor. However, it was not known if there was still listeria 
bacteria in her body.  
Therefore to help ensure your safety you will receive oral antibiotics for 7 days after each dose of 
ADXS11-001 you receive during the treatment phase, a 6-month oral antibiotic course after your study 
treatment with ADXS11-001 is over and your blood will be monitored every 4 months for 3 years after 
your study treatment is over to see if any Listeria bacteria can be found. If it is found, you will start taking 
antibiotics intravenously (i.e. the medicine is given to you through a tube in your arm). This treatment can 


3/28/16/pg. 75 
 
usually kill the bacteria. You will also be asked to see a doctor who specializes in treating infectious 
diseases like Listeria bacteria. Also, if at any time during your participation in this clinical study, you 
develop any of the symptoms that are seen with an infection, please immediately let the research staff or 
study doctor know so that they may test your blood for a Listeria blood infection.  If at any time after your 
participation in this clinical study, you develop any of these symptoms, you should immediately contact 
your primary care doctor and inform him/her that you have participated in a clinical study with and have 
received a dose of ADXS11-001 so that he/she may test your blood for a possible delayed Listeria blood 
infection.   
Likely (more than 15%) 
 
‘Flu like’ Symptoms including chills, headache, muscle aches and fever 
 
Chills or rigors 
 
Nausea  
 
Fever 
 
Headache 
 
Vomiting 
 
Fatigue 
 
Anemia 
 
Abdominal pain 
Less Likely  (5-15%) 
 
Hypotension (i.e. abnormal lowering of blood pressure) 
 
Pain (general). May include muscle, back, bone, lymph node, chest, neck, extremity, jaw, mouth. 
 
High heart rate 
 
Constipation 
 
Diarrhea 
 
Swelling of extremities 
 
Decreased appetite 
 
Short term changes in liver function or liver enzymesChanges in blood cell counts including 
kidney function tests (creatinine) 
 
Changes in blood chemistry  and blood counts 
 
Dizziness 
 
Shortness of breath at rest or with activity 
 
Rare (less than 5%) 
 
Cytokine release syndrome (a disorder characterized by nausea, headache, tachycardia, 
hypotension, rash, and shortness of breath caused from the release of cytokines from the 
cells.)This is similar to a flu-like illness. Symptoms related to cytokine release may include 
symptoms that affect the whole body such as fever, chills, shaking, feeling physically and 
mentally exhausted, headache, nausea, vomiting, rash, rapid heartbeat, low blood pressure, and 
shortness of breath which usually occur within 2-4 hours after the completion of an ADXS11-001 
dose and may last up to 24 hours.  The symptoms are caused by an increase in cytokines, which 
have been shown to occur after ADXS11-001 administration, resulting from the body’s immune 
response to the therapy. 
 
Muscle aches  
 
Short term increase in enzyme released during tissue damage  
 
Short term increase in inflammatory response protein 
 
Short term increase in pancreatic enzymes (lipase),  
 
Shaking 
 
Abdominal bloating 


3/28/16/pg. 76 
 
 
Infection such as: fungal, lung, nerve, upper respiratory tract, candidiasis 
 
Tingling in hands and feet or weakness of the nerve 
 
Depression 
 
Sweaty palms or excessive sweating 
 
Weight loss or gain 
 
Migraine 
 
Sleepiness or insomnia (difficulty falling or staying asleep) 
 
Anxiety 
 
Acute kidney failure 
 
Cough 
 
Itching, which may be severe 
 
Rash 
 
Sensitivity to light 
 
Skin ulcer 
 
Blushing or flushing 
 
Muscular weakness 
 
High blood pressure 
 
Gastroesophageal reflux disease (GERD) 
 
Lack of energy  
 
Uneasiness or discomfort (general) 
 
Inflammation of the lining of the mouth 
 
Infusion reaction 
 
Feeling of happiness 
 
Not able to empty bladder 
 
Delayed/late Listeria infection 
Serious/Life Threatening  
 
Lung infection 
 
Sepsis, which can be life threatening and lead to septic shock and even death. 
 
On rare occasions, these side effects may be severe enough to require hospitalization and/or urgent 
treatment.  In these cases, your study doctor may choose to treat these side effects by giving you 
additional fluids, high dose vasopressors (to increase your blood pressure), tocilizumab, corticosteroids, 
or other treatments not listed here.  The study doctor will determine the best treatment needed based on 
the severity of your symptoms 
 
Side Effects Related to Antibiotic use: 
The most common possible side effects seen with antibiotic use may include: 
 
Gastrointestinal disturbances (diarrhea, nausea, vomiting, and anorexia [eating disorder with 
excessive weight loss]),  
 
allergic skin reactions (rash, urticaria [swollen, pale red bumps or patches], and itching),  
 
vaginal itching or discharge,  
 
white patches on tongue,  
 
allergic reaction (shortness of breath, hives, swelling of lips, face or tongue, and fainting). 
In addition, specific antibiotics may have unique side effects and these side effects should be discussed 
with your study doctor. 


3/28/16/pg. 77 
 
Side effects associated with Bactrim: 
Common Bactrim side effects may include: 
 
nausea, vomiting, loss of appetite; or 
 
mild itching or rash. 
 
Less common Bactrim side effects may include:  
 
diarrhea that is watery or bloody; 
 
pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating; 
 
sudden weakness or ill feeling, fever, chills, sore throat, new or worsening cough; 
 
cold or flu symptoms, swollen gums, painful mouth sores, pain when swallowing, skin sores; 
 
low levels of sodium in the body--headache, confusion, slurred speech, severe weakness, 
vomiting, loss of coordination, feeling unsteady; 
 
liver problems--upper stomach pain, tired feeling, dark urine, clay-colored stools, jaundice 
(yellowing of the skin or eyes); or 
 
severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, 
skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and 
causes blistering and peeling. 
 
Get emergency medical help if you have any of these signs of an allergic reaction to Bactrim: hives; 
difficult breathing; swelling of your face, lips, tongue, or throat. 
Side effects associated with the use of nonsteroidal anti-inflammatory products (NSAIDs), such as 
naproxen: 
 
heart attack,  
 
stroke,  
 
high blood pressure,  
 
heart failure from body swelling from fluid retention,  
 
kidney problems including kidney failure,  
 
bleeding and ulcers in the stomach and intestine,  
 
low red blood cells,  
 
life-threatening skin reactions,  
 
life threatening allergic reactions,  
 
liver problems including liver failure,  
 
asthma attacks in people who have asthma.   
 
Other possible side effects can include stomach pain, constipation, diarrhea, gas, heartburn, 
nausea, vomiting, dizziness, and ringing in the ears.   
 
Side effects associated with Tocilizumab: 
Tocilizumab is a drug approved by the FDA for the treatment of rheumatoid arthritis (RA).  However, a 
dose of tocilizumab has been shown to be beneficial in the case of severe cytokine release related low 
blood pressure.  In the event you experience severe low blood pressure, your doctor may choose to 
give you a dose of tocilizumab. Because tocilizumab is continually used for RA, the known risks are 
based on continuous use.  The risks for a single dose of tocilizumab are not known.   


3/28/16/pg. 78 
 
The most common side effects (more than 10%) reported with continuous use of tocilizumab are listed 
below: 
 
Headache 
 
Common cold 
 
Increased blood pressure 
 
Infections 
 
Changes in laboratory results 
 
Risks and side effects related to biopsies include infection, bleeding, and/or pain. 
 
Reproductive risks: 
You should not become pregnant or father a baby while on this study because the drugs and the radiation 
in this study can affect an unborn baby.  Women should not breast feed a baby while on this study.  It is 
important you understand that you need to use birth control while on this study.  Check with the study 
doctor about what kind of birth control methods to use and how long to use them.  Some methods might 
not be approved for use in this study. Both men and women of childbearing age are required to use 2 
effective methods of birth control (such as a condom and spermicide) during the study and for at least 90 
days after the last dose of study drug.  
 
Bactrim: Some research studies suggest that taking Bactrim during pregnancy may be associated with an 
increased risk of birth defects. Therefore, if you become pregnant while taking this drug, you should 
immediately stop taking it and contact the study physician. He/she will be able to advise you on what to 
do 
 
Radiation therapy to the pelvis will cause fertile women to lose the ability to bear children since radiation 
causes loss of ovary function and will cause men to lose the ability to produce children.  Women may 
need hormones to relieve symptoms such as hot flashes or vaginal dryness caused by the loss of ovary 
function. 
 
Cancer treatments often have side effects.  The treatment used in this program may cause all, some, or 
none of the side effects listed.  In addition, there is always the risk of very uncommon or previously 
unknown side effects occurring. 
 
If you or your partner becomes pregnant, inform your study doctor immediately. If your partner becomes 
pregnant, your study doctor will ask her to sign a separate form to allow your study doctor to follow the 
pregnancy.  
By signing this document you are acknowledging that you understand and agree to the information 
presented in this Reproductive risk section. 
For more information about risks and side effects, ask the study doctor. 
 
Antiemetics (anti-nausea medications): Various medications used to prevent nausea and vomiting may 
cause drowsiness, dry mouth, diarrhea, constipation, headache, restlessness, agitation, anxiety, dizziness, 
involuntary tremors, skin rash, and possible allergic reaction. 
 
You will receive pre-medication to reduce the risk of infusion/injection reactions on your treatment days. 
Overall, the pre-medications you will be given are well tolerated. 
 
Venipuncture (inserting a needle into a vein to obtain blood or give medication): May cause 
inflammation, pain, bruising, bleeding, or infection. 


3/28/16/pg. 79 
 
 
When you receive chemotherapy by vein, there is a slight risk that some of the drug may leak out around 
the needle at the injection site. A skin burn may result. Most skin burns are treatable and heal well. 
 
In order to monitor the side effects, your physician will examine you frequently and obtain laboratory 
tests (blood tests, chest x-rays, or MRI scans as needed) to determine the effects of your treatment and 
alter the drug dosages if necessary. 
 
Risk of CT imaging: CT imaging uses x-rays. The radiation dose associated with this procedure is 
estimated to be a small fraction of the annual permissible dose to an x-ray technologist. 
 
Risk of MRI Imaging: Rarely the IV contrast used for MRIs, called gadolinium, has been associated 
with kidney damage and thickening of the skin. 
 
Your doctors will be carefully monitoring your condition to minimize any possible risks to you. If your 
doctors feel that the side effects are too severe in your particular case, they will lower the dose of the 
medications or even stop them. 
 
There may be other side effects that have not been reported. If you have any unusual symptoms, you 
should report them immediately to your doctor or nurse. 
 
Benefits 
Taking part in this study may or may not make your health better.  While doctors hope that the addition of 
ADXS11-001 to standard chemotherapy and radiation will be more effective against anal cancer 
compared to standard chemotherapy and radiation alone, there is no proof of this yet.  The possible 
benefits of ADXS11-001 are better control of your cancer, however, this is not guaranteed. 
 
We do know that the information from this study will help doctors learn more about ADXS11-001 as a 
treatment for anal cancer.  This information could help future cancer patients. 
 
Alternative Therapies 
What other choices do I have if I do not take part in this study?  
Your other choices may include: 
 
Getting treatment or care for your cancer without being in a study, such as standard radiation and 
chemotherapy; radiation alone; or surgery in which the anus and rectum are removed and the 
bowel is attached to a permanent opening in the skin of the stomach (colostomy).  
 
Taking part in another study, if available 
 
Getting no treatment or comfort care, also called palliative care.  In this case the cancer will 
likely continue to grow and spread to other parts of the body. This type of care may help reduce 
pain, tiredness, appetite problems and other problems caused by the cancer.  It does not treat the 
cancer directly, but instead tries to improve how you feel.  Comfort care tries to keep you as 
active and comfortable as possible. 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Refusal/Withdrawal 
You decide whether or not you want to be in the study.  Participation is voluntary.  If you decide now to 
participate, you can change your mind later and quit the study.  If you decide not to participate, or if you 
quit the study, it will not affect the health care services that you normally receive.  If the researcher or 
your doctor feels it is in your best interest, they may choose to take you out of the study at any time 
before you complete the study.   
 


3/28/16/pg. 80 
 
As soon as it becomes available, the researcher will give you new information about the study that may or 
may not affect your decision to stay in the research study. 
 
If you decide to withdraw from this study (stop taking study medication) for any reason, you will be 
asked to sign a form indicating whether you give your permission for your doctor and the research staff to 
continue to collect and submit follow-up information on your health status from your physicians and 
medical record. After signing the form, you still have the right to change your mind, at any time, 
regarding follow-up after withdrawal. 
 
Medical Treatment/Payment in Case of Injury 
If you experience a research injury _______________ (your institution) , or the study doctor, will arrange 
for medical treatment at no cost to you. The cost of your treatment will be paid for as described below. A 
research injury is any physical injury or illness caused by your participation in the study. If you are 
injured by a medical treatment or procedure that you would have received even if you were not in the 
study, that is not a research injury.  To help avoid injury, it is very important to follow all study 
directions.  
 
If you suffer a research injury and you are covered by insurance, it is possible that some or all of the costs 
of treating your condition could appropriately be billed to your insurance company.  If such costs are not 
covered either by health insurance or the study sponsor, _______________ (your institution) will pay for 
what it considers fair and proper treatment.  <INSERT HOSPITAL> has no policy to cover payment for 
such things as lost wages, expenses other than medical care, or pain and suffering.  Neither Dr. Howard 
Safran, the Principal Investigator, nor BrUOG, the coordinating center, have money set aside to reimburse 
you for medical bills from treatment of a research related injury or otherwise compensate you in the event 
of a study-related injury. 
 
Signing this form does not lessen or take away any of your lawful rights.  For more facts, please contact 
_______ name in the Office of Research Administration at ________ phone. 
 
Rights and Complaints 
If you have any complaints about your taking part in this study, or would like more facts about the rules 
for research studies, or the rights of people who take part in research studies, you may 
contact____________ name, in the _________ institutions 
 
Confidentiality 
The section at the end of this document called “Research Authorization for Use and Disclosure of 
Information” provides detailed information about how the information learned about you during this 
study will be used and shared.  More generally, all of your records from this study will be treated as 
private health care records.  The records will be protected according to the rules of_________ institutions.  
The _________ institutions privacy practices and policies are based on the rules about protection of 
private health care information contained in <INSERT STATE> law and in the Federal Health Insurance 
Portability and Accountability Act of 1996 and its regulations (“HIPAA”).   The privacy practices of 
_________ institutions and of the people who provide services at or with <INSERT HOSPITAL>   are 
explained in more detail in the_________ institutions Joint Privacy Notice (the “Privacy Notice’) that will 
be given to you. 
 
You should also know that there are times when the law might require or permit _________ institutions to 
release your health information without your permission.  The Privacy Notice explains when this might 
happen.  To give you some examples, State law requires health care workers to report abuse or neglect of 
children to the Department of Children, Youth and Families (DCYF).   State law also requires health care 
workers to report abuse or neglect of people age 60 and older to the Department of Elderly Affairs. 


3/28/16/pg. 81 
 
 
If you are found to have HIV/AIDS, <INSERT STATE> State law requires that the names of individuals 
diagnosed with HIV or AIDS be reported to the Health Department. 
Research authorization for use and disclosure of information.   
The purpose of this section of the document is to provide you with some more information about how the 
information learned about you during the study will be used and shared. 
 
We understand that your medical information is very personal and we will work hard to keep it private. If 
you sign this form you consent to participate in this research study and are giving us permission to 
use and share your personal health information in the ways described in this form.   
 
Understandings and notifications 
The main purpose of permitting the use and release of your information is to allow the research project to 
be conducted and to ensure that the information relating to that research is available to all parties who 
may need it for research purposes.  Your information may also be used as necessary for your research-
related treatment, to collect payment for your research-related treatment (when applicable), and to run the 
business operations of the hospital. 
All health care providers are required to protect the privacy of your information.  However, most persons 
or entities (i.e., businesses, organizations) that are not health care providers are not bound by law to 
protect the privacy of your information.  You understand that if the person or entity that receives your 
information is not a health care provider bound to protect your privacy, such person or entity might re-
release your health information.  
 
You have the right to refuse to sign this form.  If you do not sign this form, none of your health care 
outside the study, or the payment for your health care, or your health care benefits will be affected.  
However, if you do not sign this form, you will not be able to enroll in the research study described in this 
form, and you will not receive treatment as a study participant.  
 
If you sign this consent form, you may withdraw from the study at any time.  However, if you do not 
want the researchers to use or disclose any further information in this study you must cancel permission in 
writing and may do so at any time. If you cancel your permission, you will stop taking part in the study 
and no new information will be collected about you.  However, if you cancel your permission, it will not 
apply to actions already taken or information already collected about you by the hospital or the 
researchers before you canceled your permission.  This information or action may be needed to complete 
analysis and reports of this research. This permission will never expire unless you cancel it.  To cancel 
this permission, please write to <ENETER CONTACT INFORMATION FOR SITE PRINCIPAL 
INVESTIGATOR INCLUDING NAME, MAILING ADDRESS AND PHONE NUMBER>. 
 
If after you have signed this form you have any questions relating to your rights, please contact  ______ 
name_________ institutions at ______________ Phone.  
 
Uses and releases covered by this authorization (permission) 
Who will release, receive, and/or use your information?  This form will allow the following person(s), 
class(es) of persons, and/or organization(s)* to release,  use, and receive the information listed below in 
connection with this Study, or as required by law: 
 
 
Every research site for this study, including this hospital, and including each site's research staff 
and medical staff 
 
Health care providers who provide services to you in connection with this study 
 
Laboratories and other individuals and organizations that analyze your health information in 
connection with this study, in accordance with the study’s protocol 


3/28/16/pg. 82 
 
 
The following research sponsors and the people and companies that they use to oversee, 
administer, or conduct the research: BrUOG, the group coordinating the study, Advaxis, the 
makers of ADXS11-001 
 
The United States Food and Drug Administration, the Department of Health and Human Services, 
the Office of Inspector General, and the Office of Civil Rights 
 
The members and staff of the Institutional Review Board(s) or Ethics Committee(s) that approves 
this study 
 
Principal Investigator and other Investigators 
 
Study Coordinator 
 
Additional members of the Research Team 
 
The Patient Advocate or Research Volunteer Protector: _____________________ 
 
Members of the hospital's administrative staff responsible for administering clinical trials and 
other research activities 
 
Contract Research Organization (A contract research organization is an independent organization 
that agrees to oversee and make possible, various aspects of the clinical research process for the 
research sponsor.) 
 
Data and Safety Monitoring Boards and others that monitor the conduct of the Study, for example 
a Clinical Events Committee 
 
The members and staff of the hospitals affiliated Privacy Board (if such a board is used) 
 
Others:  
 
 
 
 
_____________________________ 
* If, during the course of the research, one of the companies or institutions listed above merges with or is 
purchased by another company or institution, this permission to use or release protected health 
information in the research will extend to the new company or institution.  
 The entire research record and any medical records held by the hospital may be used and released.   
 The following information: _____________________________________________ 
 
 
SIGNATURE 
I have read this informed consent and authorization form.  ALL OF MY QUESTIONS HAVE BEEN 
SATISFACTORILY ANSWERED, AND I WANT TO TAKE PART IN THIS RESEARCH STUDY. 
 
By signing below, I give my permission to participate in this research study and for the described uses 
and releases of information.  I also confirm that I have been now or previously given a copy of the 
Lifespan Privacy notice 
_________________________________________ 
________        ____________ 
Signature of study volunteer/authorized representative* Date         and    Time when signed 
 
 
I was present during the consent PROCESS AND signing of this agreement above by the study volunteer 
or authorized representative 
________________________________________ 
 
______________ 
Signature of witness (required if consent  
 
 
 
Date 
is presented orally or at the request of the IRB)  
 
 
 
 
 
 
 
 
I ASSURE THAT I HAVE FULLY EXPLAINED TO THE ABOVE STUDY VOLUNTEER/ 
AUTHORIZED REPRESENTATIVE, THE NATURE AND PURPOSE, PROCEDURES AND THE 
POSSIBLE RISK AND POTENTIAL BENEFITS OF THIS RESEARCH STUDY. 
___________________________________________ 
________          __________ 
Signature of researcher or designate 
 
 
 
Date         and    Time when signed 
* If signed by agent other than study volunteer, please explain below. 
_____________________________________________________________________________________
_____________________________________________________ 


3/28/16/pg. 83 
 
Documentation that a copy of this Informed Consent was given to the research participant is a 
Federal requirement.  Prior to making a copy of the signed and dated Informed Consent please 
check appropriate box(es) as applicable to indicate copy provided to: 
 
  Study Volunteer 
    
  Medical Record     
  Researcher    
  Other (Specify) 


3/28/16/pg. 84 
 
Appendix B: 
A Phase II Evaluation of ADXS11-001, Mitomycin, 5-fluorouracil (5-FU) and IMRT for Anal 
Cancer: BrUOG 276 
Fill out all fields below to confirm patient eligibility. Once documented send to BrUOG for confirmation. 
Once confirmed patient is ready to begin treatment. 
 
Conditions for Patient Eligibility: 
Date of initial biopsy ______________ 
Date patient scheduled to begin treatment if determined to be eligible __________________ 
Conditions for Patient Eligibility  
_____________( Y/N) Histologically-proven, invasive primary squamous, basaloid, or cloacogenic 
carcinoma of the anal canal; pathology to be sent 
_____________( Y/N)  AJCC 2009 TN Stage: T1N1-N3, T2(< 4cm)N1-N3, T2(> 4cm)N0-N3, T3N0-3, 
T4N0-3;based upon the following minimum diagnostic workup: stage to be sent to BrUOG 
_____________( Y/N) History/physical examination within 14 days prior to registration; to be sent to 
BrUOG 
_____________( Y/N) Within 42 days prior to registration, the patient must have an anal examination by 
any of the following: colonoscopy, sigmoidoscopy, or rigid proctoscopy with documentation of primary 
anal lesion size, distance from anal verge. Reports to be sent. If patient underwent anoscope this can be 
used for documentation. If patient is unable to tolerate any scope, reason must be documented and MRI 
can be used for disease measurements, distance and monitoring of disease response. See eligibility for 
details 
_____________( Y/N) Groin examination (clinical) within 42 days prior to registration with 
documentation of any groin adenopathy and lymphadenopathy (location: right vs. left; medial vs. lateral; 
mobile vs. fixed; and size); Must be documented and sent to BrUOG 
_____________( Y/N) X-ray (PA and lateral), CT scan, or PET/CT scan of the chest within 42 days prior 
to registration; Report to be sent 
_____________( Y/N) CT scan, MRI, or PET/CT of the abdomen and pelvis within 42 days prior to 
registration; Report to be sent 
_____________( Y/N) Zubrod Performance Status 0-1;to be documented 
_____________( Y/N) Age ≥ 18; 
_____________( Y/N) Laboratory data obtained ≤ 14 days prior to registration on study, with adequate 
bone marrow, hepatic and renal function defined as follows: Lab report to be sent to BrUOG 
 
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;   Institution ULN_____, Date_________  
 
Platelets ≥ 100,000 cells/mm3; Institution ULN_________, Date_________  
 
Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 
g/dl is acceptable.); Institution ULN_________, Date_________  
 
Serum creatinine ≤ 1.5 mg/dl; Institution ULN_________, Date_________  
 
Bilirubin < 1.4mg/dl; Institution ULN_________, Date_________  
 
ALT/AST < 3 x ULN; Institution ULN_________, Date_________  
 
Negative serum pregnancy test for women of child-bearing potential; Date_________  
_____________( Y/N) Women of childbearing potential and male participants must agree to use a 
medically effective means of birth control throughout their participation in the treatment phase of the 
study. 
_____________( Y/N) Patients must sign a study-specific informed consent prior to study entry. 
_____________( Y/N/NA) Cardiac echo with LVEF > 30% if preexisting significant cardiac disease. 
Report to be sent 
_____________( Y/N/NA) PFTS with DLCO > 40% if history of significant COPD. Report to be sent 
_____________( Y/N) Patients must be able to swallow pills. 
 
 
 


3/28/16/pg. 85 
 
 Conditions for Patient Ineligibility  
_____________( Y/N) Prior invasive malignancy (except non-melanomatous skin cancer), unless disease 
free for a minimum of 2 years; 
_____________( Y/N) Prior systemic chemotherapy for anal cancer;  
_____________( Y/N) Prior allergic reaction to the study drugs involved in this protocol. 
_____________( Y/N) Prior radiotherapy to the pelvis that would result in overlap of radiation therapy 
fields; Prior therapies including radiation to be sent to BrUOG  
_____________( Y/N) Severe, active co-morbidity, defined as follows: 
_____________( Y/N) Unstable angina and/or congestive heart failure requiring hospitalization within 
the past 6 months; 
_____________( Y/N) Transmural myocardial infarction within the last 6 months; 
_____________( Y/N) Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration; 
_____________( Y/N) Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy at the time of registration; 
_____________( Y/N) Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; 
_____________( Y/N) Patients known to be seropositive for HIV and/or active hepatitis, even if liver 
function studies are in the eligible range. 
_____________( Y/N) Other immunocompromised status (e.g., organ transplant or chronic 
glucocorticoid use). If patient has diagnosis of immunodeficiency, is dependent on or has received 
systemic steroids therapy or any form of immunosuppressive therapy within 7 days prior to the first dose 
of ADXS11-001 they are ineligible. Topical corticosteroid or occasional inhaled corticosteroids are 
allowed. 
 
_____________( Y/N) Women who are pregnant or lactating are ineligible because the treatment 
involved in this study may be significantly teratogenic and there is the potential for transmission of 
listeria to the infant. 
_____________( Y/N) Patients allergic to or with sensitivity to penicillin,  ampicillin, trimethoprim-sulfa 
and quinolones (including history of rash or anaphylaxis).  
_____________( Y/N) Patients allergic to naproxen. 
_____________( Y/N) Patients currently receiving oral or IV antibiotics. 
_____________( Y/N) Patients with a prior history of a splenectomy and/or sickle cell trait/disease. 
____________(Y/N) 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.  Sponsor must be 
contacted prior to consenting any subject who has any other device and/or implant. Site is required to 
submit to BrUOG ALL surgical implants patient has ever had in their medical history and ALL surgeries 
regardless of link to this cancer diagnosis.  
____________(Y/N) Subjects who are receiving or may receive future treatment with PI3K or TNFα 
inhibitors. 
___________(Y/N) Has 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: if patient underwent surgery > 6 weeks from start of ADSX11-001, all toxicities and/or 
complications must have recovered to baseline or Grade 1 prior to the initiation of ADXS11-001 study 
therapy and this must be documented for confirmation to BrUOG prior to registration., please confirm if 
this is applicable:________________(y/n) 
______________(y/n)Patient not being willing to have new infusion line placed for each infusion of 
ADXS11-001 as existing or newly placed central venous catheter or infusion ports are not allowed to be 
used for ADXS11-001 administration.  


3/28/16/pg. 86 
 
_____________(Y/N) Patient  not being willing to comply with requirement 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. 
___________(Y/N) 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. 
______________(y/n) Patients with active infection requiring systemic therapy (oral or IV) or those 
currently receiving antibiotics that cannot discontinue prior to dosing are ineligible. (Subjects who 
discontinue an antibiotic prior to dosing must wait at least 5 half-lives after the last dose of antibiotic 
before receiving any ADXS11-001 infusion- documentation required to be sent to BrUOG to confirm 
eligibility) 
________(y/n)Patient has a history of listeriosis or prior ADXS11-001 therapy. 
 
 
To be filled out by BrUOG Administrator: 
 
Patient registered Yes_____ No______ 
BrUOG ID Number ______________    
 
Randomization Assignment: ____________ 
Signed informed consent: The patient must be aware of the neoplastic nature of his/her disease and must 
willingly consent after being informed of the procedure to be followed, the experimental nature of the 
therapy, alternatives, potential benefits, side effects, risks, and discomforts. 
 
The support documentation, per the requirements under the study parameters section of this study, as well as 
the consent form and this checklist, must be faxed to the BrUOG Central Office at the time of registration.  
Please check if “Enclosed”, state reason when “Not Enclosed,” or check if "Not Applicable."  
Registration: 
1) Eligibility Form with 
 
 
 
Enclosed __Not Enclosed  __Not Applicable  __ 
2) Heme/Onc initial note 
 
 
 
Enclosed __Not Enclosed  __Not Applicable  __ 
3) Pathology Report(s)         
 
 
 
Enclosed __Not Enclosed  __Not Applicable  __ 
4) Radiation Oncology note  
 
 
 
Enclosed __Not Enclosed  __Not Applicable  __ 
5) MRI Report(s)  
 
 
 
Enclosed __Not Enclosed  __Not Applicable  __ 
6) Lab reports  
 
 
 
Enclosed __Not Enclosed  __Not Applicable  __ 
**Please remember to send source and confirmation of all inclusion/exclusion and schedule of 
evaluations testing as this checklist does not count as source documentation.** 
Other   
 
 
IRB approval date of protocol:  
 
  
Hospital where patient will be treated with Oncologist:   
 
 
 
______ 
Hospital where patient will be treated with Radiation Oncologist:   
 
 
______ 
Date patient will begin treatment:  
 
  Primary Physician:  
 
______ 
Your signature:   
 
 
 
 
 
 
 
 


3/28/16/pg. 87 
 
 APPENDIX C:  
 
NCI CTC Version 4.0 
Steps to determine if an adverse event is to be reported in an expedited manner: 
Step 1: Identify the type of event using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0. The CTCAE provides descriptive terminology and a grading scale for each 
adverse event listed. A copy of the CTCAE can be downloaded from the CTEP home page 
(http://ctep.cancer.gov).  
Additionally, if assistance is needed, the NCl has an Index to the CTCAE that provides help for 
classifying and locating terms. All appropriate treatment locations should have access to a copy of the 
CTCAE. 
Step 2: Grade the event using the NCI CTCAE. 
Step 3: Determine whether the adverse event is related to the protocol therapy (investigational or 
commercial). Attribution categories are as follows: Unrelated, Unlikely, Possible, Probable, and Definite. 
Step 4: Determine the prior experience of the adverse event. Expected events are those that have been 
previously identified as resulting from administration of the agent. An adverse event is considered 
unexpected, for expedited reporting purposes only, when either the type of event or the severity of the 
event is NOT listed in: 
 
 


3/28/16/pg. 88 
 
APPENDIX D 
ECOG / Zubrod Performance Status  
 
0 
Fully active, able to carry on all pre-disease performance without restriction  
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g. light house work, office work  
 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities.  Up and 
about more than 50% of waking hours  
 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
  
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or chair  
 
5 
Death  


3/28/16/pg. 89 
 
APPENDIX E  
CASE REPORT FORMS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix F: Adverse Event form 


3/28/16/pg. 90 
 
Please note that the Protocol Event Type Form (OBA) below is REQUIRED to be 
submitted to BrUOG for all SAEs. A MedWatch 3500A is not required for reporting, only 
the OBA form is required. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


3/28/16/pg. 91 
 
PROTOCOL AND EVENT TYPE 
 
NIH/OBA (RAC) Protocol Number  
1207-1172 
FDA IND number 
15057 
Date this report completed: 
 
Seriousness of the AE (choose one) 
Death      
Life-threatening      
Initial or prolonged hospitalization 
Disability 
Congenital anomaly 
Required intervention to prevent permanent 
impairment/damage 
Other medically important condition 
Non-serious 
Severity of Event 
Minimal         Moderate       Severe   
Life- Threatening      Fatal 
Was this event expected in terms of its severity? 
Yes         No             
Was this event expected in terms of its 
specificity? 
Yes         No             
Relationship of Event to gene transfer product 
Unrelated          Unlikely          Possible      
Probable          Definite 
Attribution of AE 
 
Attribution of AE, continued 
 
Concomitant medication 
Product 
Intervention 
Underlying disease 
Route of administration 


3/28/16/pg. 92 
 
Other suspected cause (describe) 
 
Type of report 
Initial        Follow-up 
DEMOGRAPHICS 
PI Name 
 
 
Name of Clinical Trial Site/Organization 
 
PI Telephone Number 
 
PI E-mail Address 
 
Reporter name  
 
Reporter Telephone number 
 
Reporter E-mail address 
 
Research Participant’s study identification 
number 
 
Research Participant’s gender 
 
Research Participant’s date of birth 
 
Research Participant’s date of death 
 
Research Participant’s weight in kgs 
 
Research Participant’s height in cms 
 
Which Arm/Cohort/treatment group was the 
subject assigned to? 
 
Was subject dosed? 
Yes          No          Information Not Available 
What study agent was received: 
IND agent     Placebo    Blinded Study Agent 
Were there any Protocol 
Deviations/Violations/Exceptions for this 
participant?   
Yes:_________________________________
_____________________________________ 
_____________________________________ 


3/28/16/pg. 93 
 
No    
DETAILED ADVERSE EVENT INFORMATION 
Adverse Event Date 
 
Description of Event 
 
 
 
 
 
 
Relevant tests (e.g. x-rays) and results 
 
 
 
Treatment (s) of Adverse Event  (Include 
medications used to treat this event.) 
 
 
 
 
Name of Concomitant Medications 
(Do not include medications used to treat this 
event.) 
 
 
 
 
Pre-existing conditions/ relevant clinical history  
(if this is an oncology trial, please designate 
primary disease, e.g. ovarian cancer) 
 
 
 
 
Date(s) of treatment(s) of the adverse event 
 


3/28/16/pg. 94 
 
 
Was autopsy performed? 
Yes                         No 
Date of autopsy 
 _______________ or Not Applicable _____ 
Outcome of the event 
Recovered/resolved 
Recovering/resolving 
Not recovered/not resolved 
Recovered/resolved with sequelae 
Fatal 
Unknown 
Documentation accompanying the report 
(e.g., H& P, Progress Notes, Discharge Summary, 
Lab or Autopsy Reports, Other, etc.)  
 
Description of any “other” documentation 
 
 
PRODUCT AND DOSING INFORMATION 
Name of gene transfer product 
ADXS11-001 
Vector type (e.g. adenovirus) 
Bacteria- Listera 
Vector sub-type (e.g. type 5, also include relevant 
deletions) 
Listeria Monocytogenes (ADXS11-001) 
Lot number 
  
Was the agent manufactured at an NGVL? 
No 
Route of administration 
IV injection 
Site of administration 
 
Did subject receive the dose specified in the 
protocol? 
 
If not, what dose was given? 
 


3/28/16/pg. 95 
 
Date of first exposure to study agent? 
 
Date of most recent exposure to study agent? 
 
Total dose received prior to this event? 
 
Total dose quantity administered to subject to 
date 
 
Unit of measure for a single dose 
1x109 cfu 
Dose quantity in a single administration 
1 
If courses used, how many were given prior to 
this event? 
 
How many doses on the last course were given? 
 
Was the administration of this product stopped 
because of this adverse event? 
 
Name of other treatment (s) (medications, 
radiation, surgery) received by research 
participant as required by the protocol