Conditions: Squamous Cell Carcinoma of the Oral Cavity
Keywords: Head and Neck Neoplasms Immunotherapy Cancer Oral Cavity
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 105
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether a pre-operative regimen of the study drug, IRX-2, a human cell-derived biologic with multiple active cytokine components, plus a single dose of cyclophosphamide, followed by 21 days of indomethacin, zinc-containing multivitamins, and omeprazole is active in treatment of oral cavity cancer. The regimen is intended to stimulate an immune response against the cancer.

Detailed description:
This study will assess the activity and safety of the IRX Regimen in participants with newly diagnosed, untreated, surgically resectable squamous cell cancer of the oral cavity. Participants will be randomly assigned to receive either Regimen 1: IRX-2 + cyclophosphamide + indomethacin + zinc + omeprazole, or Regimen 2: cyclophosphamide + indomethacin + zinc + omeprazole.

The primary study hypothesis is that the Regimen 1 with IRX-2 prolongs event-free survival and overall survival when compared to Regimen 2 without IRX-2.

Subjects will be randomized to either Regimen 1 or Regimen 2 on a 2:1 basis and treated prior to surgery.

Arms:
arm 1: IRX Regimen with IRX-2, cyclophosphamide, indomethacin, zinc-containing multivitamin, and omeprazole as neoadjuvant and adjuvant therapy. arm 2: Regimen 1 but without IRX-2

Interventions: intervention 1: IRX-2 intervention 2: Cyclophosphamide intervention 3: Indomethacin intervention 4: Zinc-containing multivitamin intervention 5: Omeprazole
Intervention descriptions: intervention 1: Method of Administration: Administered for 10 days as subcutaneous bilateral injections in the upper neck. intervention 2: Method of Administration: Cyclophosphamide is administered once by IV intervention 3: Method of Administration: Indomethacin is administered orally for 21 days. intervention 4: Method of Administration: Zinc-containing multivitamin is administered orally for 21 days. intervention 5: Method of Administration: Omeprazole is administered orally for 21 days

Protocol document:
Prot_SAP_000.pdf: 
IRX Therapeutics, Inc 
Clinical Study Protocol IRX-2 2015A-Amendment 5 
 
15 October 2018 (Final)  
CONFIDENTIAL 
i 
 
 
Clinical Study Protocol 
Title: 
A Randomized Phase 2 Trial of Neoadjuvant and Adjuvant 
Therapy with the IRX-2 Regimen in Patients with Newly 
Diagnosed Stage II, III or IVA Squamous Cell Carcinoma of 
the Oral Cavity. 
 
Protocol:  IRX-2 2015A-Amendment 5 
 
EudraCT #: 
2016-000373-21 
US BB IND #: 
11,137 
Investigational Medicinal 
Product (IMP) 
IRX-2 (Leukocyte Derived Cytokine Mixture, Human) 
 
Indication 
Neoadjuvant and adjuvant therapy of head and neck cancer 
 
 
Date: 
October 15, 2018 
Sponsor: 
IRX Therapeutics, Inc. 
140-A 58th Street, Suite 2100 
Brooklyn, New York 11220 
Phone:  +1 (929) 281-2485  
Fax:  +1 (212) 582-3659 
Investigators: 
Details of participating investigators, clinical study sites and 
other study personnel is contained in the Clinical Trial 
Master File and may be obtained from the Sponsor 
 
This document is confidential.  
It contains proprietary information of IRX Therapeutics, Inc. Any disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited. 


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Clinical Study Protocol IRX-2 2015A-Amendment 5 
 
15 October 2018 (Final)  
CONFIDENTIAL 
ii 
Investigator Agreement 
I have read and approved this protocol. My signature confirms my agreement that the clinical 
study will be conducted in full compliance with the protocol and all applicable laws, 
regulations and regulatory requirements including, but not limited to, the International 
Conference on Harmonisation Guideline for Good Clinical Practice (GCP), the Code of 
Federal Regulations (CFR), the European clinical trial regulations, the ethical principles that 
have their origins in the Declaration of Helsinki and all applicable country-specific and local 
regulations. All required study information will be archived as required by regulatory 
authorities. 
I agree to monitoring and auditing by the sponsor and inspection by the appropriate regulatory 
authority(ies) as required. 
I understand that there is nothing in this document which is intended to limit my authority as 
a physician to provide emergency medical care under applicable regulations. 
I understand the confidential nature of this document and that the information contained therein 
is proprietary to IRX Therapeutics, Inc.. Before any disclosure of such information, 
authorization in writing by the sponsor will be obtained. This document will be used solely for 
the purpose of reviewing or performing this study. At least 60 days prior to submitting or 
presenting a manuscript or other materials relating to this study to a publisher, reviewer, or 
other outside persons, I shall provide to IRX Therapeutics Inc. a copy of all such materials and 
manuscripts, and allow them 60 days to review and provide comment.  
 
 
Investigator: 
 
Date:  
Institution: 
 
  
 
 




IRX Therapeutics, Inc 
Clinical Study Protocol IRX-2 2015A-Amendment 5 
 
15 October 2018 (Final)  
CONFIDENTIAL 
iv 
 
†Important Note:  
 
As of Protocol Amendment 4 all adjuvant, booster administration of study regimen has been 
discontinued. Randomized subjects will receive neoadjuvant treatment and will then be 
discontinued from further study drug. After discontinuation from study drug, all subjects will be 
followed for progression and survival as described in the protocol. 
 
 
 


IRX Therapeutics, Inc 
Clinical Study Protocol IRX-2 2015A-Amendment 5 
 
15 October 2018 (Final)  
CONFIDENTIAL 
1 
Protocol Synopsis IRX-2 2015A 
Study Title 
A Randomized Phase 2 Trial of Neoadjuvant and Adjuvant Therapy with the 
IRX-2 regimen in Patients with Newly Diagnosed Stage II, III or IVA Squamous 
Cell Carcinoma of the Oral Cavity 
Study Phase 
2b 
Rationale for  
Study 
The IRX-2 regimen has been studied in patients with head and neck squamous cell 
carcinoma (HNSCC) in two open-label, multi-center studies. A Phase 1 trial 
evaluated the IRX-2 regimen as therapy for advanced disease and a Phase 2a trial 
evaluated the IRX-2 regimen as neoadjuvant therapy prior to surgery. These trials 
established that the IRX-2 regimen has an acceptable safety profile and produced 
changes in lymphocyte infiltrate in surgically resected tumors compared to baseline 
tumor biopsies. In addition, the only subject to undergo PET imaging had 
significantly reduced metabolic activity after treatment with the IRX-2 regimen. 
Overall survival (OS) appeared favorable compared to historical controls and was 
greater in subjects who had higher tumor lymphocyte infiltration in the surgical 
specimen and in those with the greatest increase in tumor lymphocyte infiltration 
after treatment with the IRX-2 regimen.  
The present study is intended to further evaluate neoadjuvant therapy with the IRX-2 
regimen in a randomized trial. In addition, the immunotherapy regimen will be 
enhanced by adding four adjuvant booster courses of a shorter IRX-2 regimen during 
the first postoperative year.†  
Study Design 
This is an open label, randomized, multi-center, multi-national Phase 2b clinical trial 
intended for patients with Stage II, III or IVA untreated SCC of the oral cavity who 
are candidates for resection with curative intent. Subjects will be randomized 2:1 to 
either Regimen 1 or Regimen 2 and treated for 21 days prior to surgery and then 
postoperatively with a booster regimen given every 3 months for 1 year (a total of 4 
times.)†  
• 
Regimen 1: IRX-2 Regimen with cyclophosphamide, indomethacin, zinc- 
containing multivitamins, omeprazole and IRX-2 as neoadjuvant and 
adjuvant† therapy as in the Tables below. 
• 
Regimen 2: Regimen 1 with cyclophosphamide, indomethacin, zinc- 
containing multivitamins, omeprazole but without IRX-2 as neoadjuvant 
and adjuvant† therapy. 
Randomization will be 2:1 in favor of Regimen 1. Treatments will be allocated to 
study subjects using minimization with a stochastic algorithm based on the range 
method. Minimization will account for the major prognostic factors for SCC of the 
oral cavity (T and N stage) and study center to avoid imbalances in treatment 
allocation within centers.  
Postoperatively, subjects will first receive standard adjuvant radiation or 
chemoradiation therapy as determined by the investigators per protocol guidelines 


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2 
and then will also receive Booster Regimen 1 or 2 as determined in the prior 
randomization.†  
Subjects will be followed for the Primary, Secondary and Exploratory endpoints as 
discussed below and detailed in the Schedule of Study Events (Protocol Section 5.1). 
Protocol mandated follow-up will end 4 years after randomization of the last patient.  
IRX-2 Regimen 
(Regimen 1) 
IRX-2 is a primary cell-derived biologic with multiple active cytokine components, 
produced under pharmaceutical standards from phytohemagglutinin (PHA) and 
ciprofloxacin stimulated donor mononuclear cells.  
The Neoadjuvant IRX-2 Regimen is a 21-day pre-operative regimen of 
cyclophosphamide on Day 1, indomethacin, zinc-containing multivitamins and 
omeprazole on Days 1-21, and subcutaneous IRX-2 injections in bilateral mastoid 
insertion regions for 10 days between Days 4 and 21†, as shown in the table below: 
IRX-2 Neoadjuvant Regimen: 
Agent 
Dose 
Route of Administration 
Treatment Days 
Cyclophosphamide 
300 mg/m2 
IV 
1 
IRX-2 
230 units daily 
(Bilateral 
injections of 
115 units) 
Subcutaneous at or near 
the mastoid insertion of 
both sternocleidomastoid 
muscles 
Any 10 days  
between  
Days 4 and 21 
 
Indomethacin 
25 mg TID 
Oral 
1-21 
Zinc-containing 
multivitamins 
1 tablet 
containing 15-
30 mg of zinc 
Oral 
1-21 
Omeprazole 
20 mg 
Oral 
1-21 
The Booster IRX-2 Regimen is given at 3, 6, 9 and 12 months (-14 to +28 days) 
after surgical resection as detailed in Protocol Section 5.2.8.† It is a 10-day post-
operative regimen of cyclophosphamide on Day 1, indomethacin, zinc-containing 
multivitamins and omeprazole on Days 1-10 and subcutaneous IRX-2 injections in 
bilateral deltoid regions for 5 days between Days 4 and 10 as shown in the table 
below: 
IRX-2 Booster Regimen†: 
Agent 
Dose 
Route of 
Administration 
Treatment Days 
Cyclophosphamide 
300 mg/m2 
IV 
1 dose every 3 months 
for 1 year  
IRX-2 
230 units daily 
(Bilateral 
injections of 
115 units) 
Subcutaneous 
into bilateral 
deltoid regions 
Every 3 months 
Any 5 days between 
Days 4 and 10 
Indomethacin 
25 mg TID 
Oral 
Every 3 months  
Days 1-10 


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Zinc-containing 
multivitamins 
1 tablet 
containing 15-
30 mg of zinc 
Oral 
Every 3 months  
Days 1-10 
Omeprazole 
20 mg daily 
Oral 
Every 3 months  
Days 1-10 
Control Arm 
Regimen  
(Regimen 2) 
The control arm will be dosed following the same regimen as Regimen 1 except that 
subjects will not receive IRX-2. 
Objectives  
Primary Objective:  To determine if the event-free survival (EFS) of subjects 
treated with Regimen 1 is longer than for subjects treated with Regimen 2. 
Secondary Objectives:  
1) to determine if OS of subjects treated with Regimen 1 is longer than for 
subjects treated with Regimen 2. 
2) to compare the safety of each Regimen. 
3) to compare the feasibility of each Booster Regimen†. 
Key Exploratory Objectives: To determine and compare between the Regimens:  
1) changes in tumor size from baseline to surgery measured by CT scans (MRI 
also acceptable, so long as the same modality is used for baseline and pre-
surgery scans).  
2) changes from baseline to surgery in functional imaging as estimated by PET 
scan.  
3) lymphocyte infiltrates in the pre-treatment tumor biopsy, the surgical 
specimen and changes between these two samples. These data will be 
analyzed to seek any baseline characteristics that are correlated with 
differences in outcome between the Regimens.  
Additional Exploratory Objectives: To determine and compare between the 
Regimens:  
1) surgical pathology, including tumor characteristics (depth of invasion, 
perineural invasion, pattern of invasion, extent of necrosis), tumor margins 
and lymph node involvement.  
2) prognostic and predictive factors and clinical-pathologic-immunologic 
correlates, including, for example, nutritional status (body mass index, 
albumin), absolute lymphocyte count, lymphocyte subsets and histological 
differences in the surgical specimen and gene expression profiles with 
disease-free survival, recurrence, second primary tumors, and patterns of 
disease recurrence.  
3) Human papilloma virus (HPV) status (p16 protein expression) and  any 
relationship between tumor p16 protein expression and differences in 
outcome between the Regimens.  
4) the peripheral T cell receptor profile prior to and post treatment during the 
first year of the trial. 
5) RNA expression profiling of immune-inflammatory markers. 


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Methods  
Primary Endpoint:   
EFS will be assessed by physical examination at routine follow-up visits every 3 
months after surgery for the first two years and by chest CT scans performed yearly 
x 4 years.  During years 3-4 subjects will be contacted by phone to determine survival 
status, and will be assessed in person (eg, physical exam, laboratory evaluations, 
etc.) according to standard of care at their enrolling institution. Any indication of 
recurrence occurring at these SOC visits should be followed up with a confirmatory 
imaging and reported in the Recurrence CRF folder. Progression prior to surgical 
resection will not be considered an Event, but failure to resect tumor that was 
apparent at randomization for any reason will be considered an Event. Progression 
after resection should be confirmed by biopsy, and scans (CT, MRI or PET) should 
be performed to restage disease and establish patterns of relapse. The date of 
progression will be the date on which the decision not to resect tumor that was 
apparent at randomization is made or on which the Investigator first observes 
recurrent locoregional or metastatic disease by physical or radiologic examination. 
Death from any cause will also be considered an Event. Diagnosis of a second 
malignancy will not be considered an Event, but date of diagnosis, site and histology 
will be collected. 
Secondary Endpoints:   
Survival data will be collected in all subjects (phone contact after progression will 
be sufficient). Safety of each Regimen and feasibility of the Booster Regimens† will 
be assessed by the incidence and severity of adverse events, serious adverse events 
and subject discontinuations (as defined in the Protocol). 
Exploratory Endpoints:  
• 
Change in tumor size will be determined by a comparison of the imaging 
studies (CT or MRI) obtained pre-treatment and just prior to surgery. 
Percent changes in tumor size will be determined by central radiology 
review by radiologists blinded to the treatment Regimen. 
• 
Change in functional imaging will be determined by a comparison of the 
PET scans obtained pre-treatment and just prior to surgery. Percent changes 
in glycolytic activity will be estimated by central radiology review by 
radiologists blinded to the treatment Regimen. 
• 
Lymphocyte infiltrates in the pre-treatment tumor biopsies and the surgical 
specimens will be determined and compared. Subsets of lymphocytes will 
be evaluated including total T cells and naïve, cytotoxic and regulatory T 
cells. The analyses may include quantifications of cellular infiltrates and 
degree of activation by immunohistochemistry including (but not limited 
to): CD3, CD8, CD45RO, CD68 (myeloid derived suppressor cells) and Fox 
P3 on lymphocytes and MHC class I and II and PDL1 on tumor cells. Other 
immune subsets and activation markers may be evaluated. Tumor gene 
expression signatures may also be performed. Lymphocyte infiltrates and 
changes after treatment will also be evaluated using T cell receptor (TCR) 
repertoire analyses performed on extracted RNA. These studies will be 
performed by one or more external contract research organizations without 
knowledge of the treatment Regimen received.  


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Clinical Study Protocol IRX-2 2015A-Amendment 5 
 
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• 
Surgical pathology specimens will be centrally reviewed to explore the 
impact of the features described above on clinical outcome. HPV status will 
be assessed by p16 expression and its relationship to clinical outcome will 
be explored. Body mass index, serum albumin, peripheral blood absolute 
lymphocyte count and possibly other hematological, chemical or clinical 
data, including the peripheral T cell receptor profile prior to and post 
treatment during the first year of the trial, will be used to explore 
relationships to clinical outcome. RNA expression profiling of immuno-
inflammatory markers will also be performed. 
 
Analyses of exploratory endpoints will be conducted. The Sponsor may at any time 
alter or discontinue some or all of these evaluations so long as additional clinic 
visits, radiology studies or blood draws are not initiated.  
Analyses of some or all of the exploratory endpoints will be conducted by the 
Sponsor or designated representatives at intervals depending on the availability of 
sufficient data.  
Study Population 
Subjects with Stage II, III or IVA squamous cell cancer of the oral cavity who have 
resectable primary tumors and are without medical contraindications to curative 
surgery. 
Number of Subjects 
A total of approximately 100 subjects will be randomized. 
Number of Centers  
Approximately 50. 
Inclusion Criteria 
1. Pathologically confirmed clinical Stage II, III or IVA squamous cell cancer of 
the oral cavity (excluding lip).Subjects must be staged using  AJCC Cancer 
Staging Manual Edition 7.0 (Appendices 1 and 2). 
2. Disease surgically resectable with curative intent  
3. Hematological function: hemoglobin >9 g/dL; lymphocyte count >0.50 x 
109/L; neutrophil count >1.5 x 109/L; platelet count >100 x 109/L 
4. Hepatic function: serum albumin >3.0 g/dL; aspartate aminotransferase 
(AST/SGOT) and alanine aminotransferase (ALT/SGPT) <3x the upper limits 
of normal (ULN); alkaline phosphatase <2x the ULN  
5. Prothrombin time (PT) and partial thromboplastin time (PTT) < 1.4x the ULN 
6. Calculated creatinine clearance > 50 mL/minute (Appendix 4) 
7. At least 18 years of age 
8. Willing and able to give informed consent and adhere to protocol therapy 
9. Karnofsky performance status (KPS) 70% 
10. Females of childbearing potential (not surgically sterile or less than 12 
months post-menopausal) must be able and willing to use a highly effective 
form of pregnancy prevention  from the time of screening, during the study 
and 1 year after last dose of study regimen. Males with a partner of 
childbearing potential must use condoms with spermicide from the date of 
screening to 1 year after their last dose of study regimen (See Section 3.2.1 
for details) 
11. Negative urine/serum pregnancy test, if applicable  


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Exclusion Criteria 
1. Prior surgery, radiation therapy, or chemotherapy other than biopsy or 
emergency procedure required for supportive care of this oral cavity cancer. 
2. Any medical contraindications or previous therapy that would preclude 
treatment with either IRX-2 Regimen 1 or 2 or the surgery, reconstruction or 
adjuvant therapy required to treat the oral tumor appropriately.  
o Live vaccines should ideally not be administered to any patients 
undergoing treatment with chemotherapy or immunotherapy, but if need 
be, they should be administered >4 months prior to the initiation of 
treatment or >4 months after the completion of all treatment.  
o Inactivated vaccines should precede the initiation of any study regimen 
and/or standard adjuvant therapy by at least 2 weeks, but preferably 4 
weeks or longer. 
3. Clinical status of either subject or tumor such that administration of 21 day    
neoadjuvant IRX-2 Regimen 1 or 2 before surgery would be medically 
inappropriate.  
4. Tumor of the oropharynx. 
5. Tumor involvement of the following sites or any of these signs or symptoms 
likely to be associated with T4b cancer: 
o involvement of pterygopalatine fossa, maxillary sinus, or facial skin;. 
o gross extension of tumor to the skull base; 
o pterygoid plate erosion; 
o sphenoid bone or foramen ovale involvement; 
o direct extension to involve prevertebral fascia; 
o extension to superior nasopharynx or Eustachian tube; 
o direct extension into the neck with involvement of the deep neck 
musculature (neck node fixation); 
o suspected invasion (encasement) of the common or internal carotid 
arteries. Encasement will be assessed radiographically and will be defined 
as tumor surrounding the carotid artery 270º or greater; 
o direct extension of neck disease to involve the external skin; 
o direct extension to mediastinal structures; 
o regional metastases to the supraclavicular neck (low level IVB or VB) 
6. Any investigational agent within the previous 30 days. 
7. Daily administration of systemic immunosuppressive therapy or corticosteroids 
(except in physiological doses for hormone deficiency) during the previous 30 
days. 
8. Chronic anticoagulation, not including aspirin, but including heparins, warfarin, 
oral anticoagulation or other platelet function inhibitors, that can not, in the 
documented opinion of the investigator, safely be interrupted from at least 2 
days prior to the initiation of the study regimen until after surgical resection of 
the tumor.  
9. Symptomatic cardiopulmonary disease (including congestive heart failure and 
hypertension), coronary artery disease, serious arrhythmia or chronic lung 
disease. Patients with these conditions who are stable with relatively minor 
symptoms and who are appropriate candidates for surgical treatment of their 
tumor need not be excluded 


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7 
10. Myocardial infarction within the last 3 months 
11. Distant metastases (M1 disease). 
12. Known infection with hepatitis B, hepatitis C, or HIV. 
13. Signs or symptoms of systemic  infection (use of antibiotics to treat superficial 
infection or contamination of tumor shall not, by itself, be considered evidence 
of infection). 
14. Clinically significant gastritis or peptic ulcer disease that would contraindicate 
the use of indomethacin. 
15. Stroke or other symptoms of cerebral vascular insufficiency within the last 
3 months. 
16. Allergy to ciprofloxacin (or other quinolones), acetylsalicylic acid, or 
indomethacin. 
17. Previous diagnosis of invasive cancer from which the individual is NOT 
disease-free AND that has required treatment within the past 5 years, except 
for superficial skin, cervical cancer in-situ, well-differentiated thyroid or early 
stage prostate or bladder cancer (i.e., treatment with curative intent and long 
term disease-free expectations). 
18. Prior axillary dissection. 
19. Breastfeeding women. 
Study Monitoring 
(Data Safety 
Monitoring Board) 
A Data and Safety Monitoring Board (DSMB) will be established to monitor the 
conduct of the study as well as safety data. The DSMB will consist of physicians 
and a statistician who are not otherwise involved in the trial. The DSMB will meet 
via teleconference or in person over the course of the study and may also meet on an 
unscheduled basis if any unexpected safety concerns arise. The DSMB will monitor 
the study for delay in definitive surgery as described in Section 8.4. Detailed 
information regarding standard of care adjuvant therapy for subjects in each arm will 
be reviewed. Additional details of DSMB procedures and communication with 
Investigators and the Sponsor will be described in a separate Charter. 
Statistical 
Considerations 
Assuming that the EFS at 24 months will be 50% for subjects receiving Regimen 2, 
this trial will have 61% power (one-sided  = 0.1) to detect an increase in EFS of 
15% (i.e. to 65%) at 24 months (hazard ratio [HR] = 0.62) for the subjects receiving 
Regimen 1. The required number of EFS events for  the primary endpoint is 51 
progressions or deaths. The primary analysis will be of the entire population as 
randomized (intent-to-treat). 
Assuming an average accrual of 2 patients per month during the first year, and 7 
patients per month during the second year, the trial will have accrued 100 subjects 
in 24 months.  
Assuming that the OS at 36 months will be 55% for subjects receiving Regimen 2, 
this trial will have 66% power (one-sided  = 0.1) to detect an increase in OS of 
15% (i.e. to 70%) at 36 months (HR = 0.60) for the subjects receiving Regimen 1. 
The required number of OS events for the assessment of the OS endpoint is 51 
deaths. 
An Interim Analysis (IA) will be performed as specified in Protocol Section 9.5. 


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TABLE OF CONTENTS  
Protocol Synopsis IRX-2 2015A ............................................................................................... 1 
1 
INTRODUCTION ............................................................................................................ 15 
1.1 
BACKGROUND ................................................................................................................. 15 
1.1.1 
Squamous Cell Carcinoma of the Oral Cavity ........................................................................ 15 
1.1.2 
Staging, Treatment, and Prognosis ....................................................................................... 15 
1.1.3 
Rationale for Inclusion of Stage II Patients ........................................................................... 15 
1.1.4 
Immune Deficiency and Immunotherapy in HNSCC Patients ............................................... 16 
1.1.5 
The IRX-2 Regimen ................................................................................................................ 16 
1.1.6 
Manufacture and Composition of IRX-2 ................................................................................ 18 
1.1.7 
Mechanism of Action of IRX-2 ............................................................................................... 18 
1.1.8 
Rationale for the Components of the IRX-2 Regimen ........................................................... 19 
1.1.9 
Delivery of IRX-2 .................................................................................................................... 20 
1.2 
Nonclinical Studies with the IRX-2 Regimen ...................................................................... 20 
1.3 
Clinical Experience with the IRX-2 Regimen in Subjects with HNSCC .................................. 20 
1.3.1 
Phase 1 Trial .......................................................................................................................... 20 
1.3.2 
Phase 2 Trial .......................................................................................................................... 20 
1.3.2.1 
Study Design and Patient Demographics ................................................................................... 20 
1.3.2.2 
Clinical Results ............................................................................................................................ 21 
1.3.2.2.1 
Radiographic changes: ........................................................................................................... 21 
1.3.2.2.2 
Disease-free and Overall Survival: ......................................................................................... 21 
1.3.2.3 
Safety Results ............................................................................................................................. 21 
1.3.2.4 
Immunologic Results .................................................................................................................. 22 
1.3.2.5 
Time to Surgery .......................................................................................................................... 24 
2 
STUDY Objectives ......................................................................................................... 26 
2.1 
Primary Objective ............................................................................................................ 26 
2.2 
Secondary Objectives ....................................................................................................... 26 
2.3 
Exploratory Objectives ..................................................................................................... 26 
3 
Investigational Plan ...................................................................................................... 27 
3.1 
Study Design .................................................................................................................... 27 
3.1.1 
Rationale for Study Design .................................................................................................... 28 
3.1.2 
Rationale for Endpoints ......................................................................................................... 28 
3.1.3 
Benefit/Risk Assessment and Study Monitoring ................................................................... 29 
3.1.4 
Estimated Duration of Study ................................................................................................. 29 
3.2 
Selection of Study Population ........................................................................................... 30 
3.2.1 
Inclusion Criteria ................................................................................................................... 30 
3.2.2 
Exclusion Criteria ................................................................................................................... 31 
3.3 
Tumor Staging ................................................................................................................. 32 
3.4 
Assessment of Surgical Resectability................................................................................. 33 
3.5 
Termination of Study Treatment ...................................................................................... 33 
3.6 
Withdrawal of Consent .................................................................................................... 34 
3.7 
Medical Monitoring ......................................................................................................... 34 
3.7.1 
Medical Monitors .................................................................................................................. 34 
3.7.2 
Principal Investigator(s)......................................................................................................... 34 
3.8 
Data Safety Monitoring Board .......................................................................................... 35 


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4 
STUDY TREATMENTS .................................................................................................... 36 
4.1 
Study Design and Randomization ..................................................................................... 36 
4.2 
Regimen 1 ....................................................................................................................... 36 
4.3 
Regimen 2 ....................................................................................................................... 38 
4.3.1 
Description of Regimen 2 ...................................................................................................... 38 
4.4 
Regimen Medications....................................................................................................... 39 
4.4.1 
IRX-2 ...................................................................................................................................... 39 
4.4.2 
IRX-2 Storage ......................................................................................................................... 39 
4.4.3 
Supply of Other Medications ................................................................................................ 39 
4.4.4 
Administration of  Other Medications .................................................................................. 39 
4.5 
Method of Assigning Subject Numbers ............................................................................. 40 
4.6 
Treatment Compliance ..................................................................................................... 40 
4.7 
Prohibited, Prior and Concomitant Treatments ................................................................. 40 
5 
Study Procedures and Schedule .................................................................................... 40 
5.1 
Study Schedule ................................................................................................................ 40 
5.2 
Study Procedures ............................................................................................................. 46 
5.2.1 
Screening ............................................................................................................................... 46 
5.2.2 
Randomization ...................................................................................................................... 47 
5.2.3 
Day 1 ...................................................................................................................................... 47 
5.2.4 
Days 4 to 21 (REGIMEN 1 Dosing ) ........................................................................................ 48 
5.2.5 
Clinical Assessments on Days 15-18 ...................................................................................... 48 
5.2.6 
One to Five Days Prior to Surgery ......................................................................................... 48 
5.2.7 
Surgery .................................................................................................................................. 49 
5.2.8 
Follow-up Schedule ............................................................................................................... 51 
5.2.8.1 
Protocol-Required Follow-up Monitoring .................................................................................. 51 
5.2.8.2 
Survival ....................................................................................................................................... 51 
5.2.8.3 
Additional Follow-up Testing...................................................................................................... 52 
5.2.9 
Regimen 1 and 2 Dose Modification ..................................................................................... 52 
6 
STUDY Assessments ..................................................................................................... 53 
6.1 
Endpoint Assessments ..................................................................................................... 53 
6.1.1 
Primary Endpoint - EFS .......................................................................................................... 53 
6.1.2 
Secondary Endpoints ............................................................................................................. 53 
6.1.2.1 
Overall Survival ........................................................................................................................... 53 
6.1.2.2 
Safety and Feasibility .................................................................................................................. 53 
6.1.3 
Exploratory Endpoints ........................................................................................................... 53 
6.1.3.1 
Key Exploratory Endpoints ......................................................................................................... 54 
6.1.3.1.1 
Tumor Size ............................................................................................................................. 54 
6.1.3.1.2 
Functional Imaging ................................................................................................................ 54 
6.1.3.1.3 
Lymphocyte Infiltrates ........................................................................................................... 54 
6.1.3.2 
Additional Exploratory Endpoints .............................................................................................. 54 
6.1.3.2.1 
Pathology ............................................................................................................................... 54 
6.1.3.2.2 
Prognostic Factors ................................................................................................................. 54 
6.1.3.2.3 
HPV Status ............................................................................................................................. 54 
6.1.3.2.4 
T cell Receptor Profile ............................................................................................................ 55 
6.1.3.2.5 
RNA Expression ...................................................................................................................... 55 
7 
Discipline Standards of Care ......................................................................................... 56 
7.1 
Surgery ............................................................................................................................ 56 


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7.2 
Radiation Therapy ............................................................................................................ 56 
7.3 
Chemotherapy with Radiation .......................................................................................... 57 
8 
Adverse Events, Reporting Requirements, and STopping Rules ..................................... 58 
8.1 
Adverse Event Definitions ................................................................................................ 58 
8.1.1 
Definition of Serious and Life Threatening Adverse Events .................................................. 59 
8.1.2 
Protocol Defined Adverse Events for SAE Reporting ............................................................ 59 
8.1.3 
Definition of Relationship to Study Regimen and Drug ........................................................ 59 
8.1.4 
Definition of Severity............................................................................................................. 60 
8.1.5 
Definition of Action Taken .................................................................................................... 60 
8.1.6 
Definition of Outcome to Date .............................................................................................. 60 
8.2 
Notification of Serious or Unexpected Adverse Events ...................................................... 61 
8.3 
Pregnancies ..................................................................................................................... 62 
8.4 
Reporting of Deaths ......................................................................................................... 62 
8.5 
Stopping Rules for Excessive Toxicity Leading to Delay  in Definitive Surgery ..................... 62 
9 
Statistical Considerations ............................................................................................. 64 
9.1 
Sample Size Considerations .............................................................................................. 64 
9.2 
Subject Populations ......................................................................................................... 64 
9.3 
Methods to be Used for Handling Missing or Spurious Data .............................................. 64 
9.4 
Efficacy ............................................................................................................................ 65 
9.5 
Interim Analysis ............................................................................................................... 65 
9.6 
Safety .............................................................................................................................. 66 
10 ETHICAL AND REGULATORY CONSIDERATIONS ............................................................. 67 
10.1 
Protection of Human Subjects .......................................................................................... 67 
10.2 
Informed Consent ............................................................................................................ 67 
10.3 
Institutional Review Board or Independent Ethics Committee ........................................... 67 
11 Study Administration ................................................................................................... 68 
11.1 
Monitoring Plan ............................................................................................................... 68 
11.1.1 
Pre-study Site Evaluation .................................................................................................. 68 
11.1.2 
Site Initiation ..................................................................................................................... 68 
11.1.3 
Interim Monitoring ........................................................................................................... 68 
11.1.4 
Study Close-out ................................................................................................................. 68 
11.1.5 
Site Responsibility ............................................................................................................. 68 
11.2 
Compliance Statement ..................................................................................................... 69 
11.3 
Investigational Product Accountability ............................................................................. 69 
11.4 
Study Documents and Access to Records .......................................................................... 69 
11.5 
Study Closure/Study Termination ..................................................................................... 70 
11.6 
Quality Assurance ............................................................................................................ 70 
11.7 
Confidentiality and Publication Policy ............................................................................... 70 
12 References ................................................................................................................... 72 
 


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LIST OF FIGURES  
 
Figure 1 
Overall Survival by High and Low Lymphocyte Infiltration in the Surgical 
Resection Specimen (Study IRX-2 2005-A) ......................................................... 22 
Figure 2 
Lymphocyte Infiltration (Study IRX-2 2005-A)................................................... 23 
Figure 3 
Overall Survival by Change in Lymphocyte Infiltration from Biopsy to Resection 
Specimen (Study IRX-2 2005-A) ......................................................................... 24 
Figure 4 
Flow Chart of Study Design ................................................................................. 27 
 
LIST OF TABLES  
 
Table 1: 
IRX-2 Neoadjuvant Regimen ............................................................................... 37 
Table 2 
IRX-2 Booster Regimen ....................................................................................... 37 
Table 3 
IRX-2 Neoadjuvant Control Regimen .................................................................. 38 
Table 4 
IRX-2 Booster Control Regimen .......................................................................... 38 
Table 5 
Schedule of Events ................................................................................................ 41 
LIST OF APPENDICES  
Appendix 1: 
American Joint Committee on Cancer: Staging of Head and Neck Cancer-Lip and 
Oral Cavity – TNM Staging .................................................................................. 77 
Appendix 2: 
American Joint Committee on Cancer: Staging of Head and Neck Cancer-Lip and 
Oral Cavity – Stage Grouping AJCC Staging Manual, 7th Edition ..................... 78 
Appendix 3: 
Karnofsky Performance Status ............................................................................. 79 
Appendix 4: 
Calculation of Creatinine Clearance by Cockcroft-Gault Equation ..................... 80 


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List of Definitions and Abbreviations 
AE 
adverse event 
AJCC 
American Joint Committee on Cancer 
Akt 
protein kinase B 
ALT/SGPT 
alanine aminotransferase/serum glutamic pyruvic transaminase 
ANC 
absolute neutrophil count 
AST/SGOT 
aspartate aminotransferase/ serum glutamic oxaloacetic transaminase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CD 
cluster of differentiation  
CFR 
Code of Federal Regulations 
CRF 
case report form 
CRO 
Contract Research Organization 
CT 
computed tomography 
DFS 
disease-free survival 
DSMB 
Data and Safety Monitoring Board 
EFS 
event-free survival 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose positron emission tomography 
Fox P3 
Fox P3 protein is involved in immune system responses 
GM-CSF 
granulocyte-macrophage colony stimulating factor 
HIV 
human immunodeficiency virus 
HNSCC 
head and neck squamous cell carcinoma 
HPV 
human papillomavirus 
HR 
hazard ratio 
IB 
Investigator’s Brochure 
IEC 
Independent Ethics Committee 
IFN-α 
interferon alpha 
IFN-γ 
interferon gamma 
IL-1 
interleukin 1 beta 
IL-2 
interleukin 2 
IL-7 
interleukin 7 


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IL-10 
interleukin 10 
IL-12 
interleukin 12 
IL-15 
interleukin 15 
IRB 
Institutional Review Board 
IRX-2 
primary cell-derived biologic with multiple active cytokine components 
IRX-2 regimen 
Twenty subcutaneous injections of 115 U of IRX-2 (over 10 days) 
preceded by cyclophosphamide with a 21 day course of indomethacin 
and zinc containing multivitamins 
ITT 
Intention-To-Treat 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
Intravenous 
IxRS 
Interactive Recognition System 
KPS 
Karnofsky performance status 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities  
MHC 
major histocompatibility complex  
MHC class I 
major histocompatibility complex class 1 
MHC class II 
major histocompatibility complex class 2 
MRI 
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NK or NKT 
natural killer T cells 
OS 
overall survival 
PET 
positron emission tomography 
PDL1 
programmed death ligand 1  
PHA 
Phytohemagglutinin 
PI 
Principal Investigator 
PI3K 
phosphoinositide 3 kinase 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 


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SCC 
squamous cell carcinoma 
T cells 
cellular immune lymphocytes; derivation – thymus lymphocytes 
T-bet 
T box transcription factor 
TCR 
T cell receptor  
Teff 
T effector cell 
TGF- 
Transforming growth factor beta 
Treg 
T regulatory cell; suppressor T cell 
TID 
three times a day 
TNF-α 
tumor necrosis factor alpha 
TNM  
tumor grading system (T-primary lesion; N-nodes; M-metastases) 
U 
unit(s) 
ULN 
upper limit of normal 
US 
United States 
 


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1 
INTRODUCTION 
1.1 
BACKGROUND 
1.1.1 
Squamous Cell Carcinoma of the Oral Cavity 
Squamous cell carcinoma (SCC) is the most frequently occurring malignant tumor in the head and 
neck. More than 90% of head and neck squamous cell carcinomas (HNSCC) originate from the 
mucosal linings of the oral cavity, pharynx, or larynx. The estimated worldwide incidence of 
HNSCC in 2000 was more than 551,000 with greater than 217,000 deaths [Parkin, 2001]. The 
epidemiology of HNSSC is discussed in more detail in the Investigator’s Brochure (IB).  
Oral cavity cancer can affect any part of the oral cavity, including the lip, tongue or mouth. 
Although five-year survival rates are around 50%, patients successfully treated may still have to 
cope with consequences of their treatment that affect appearance, function and quality of life. 
This study will evaluate the effects of the IRX-2 Regimen in patients with Stage II to Stage IVA 
untreated SCC of the oral cavity compared to a control arm where no IRX-2 will be given. 
1.1.2 
Staging, Treatment, and Prognosis 
Classification and staging of SCC of the oral cavity is performed according to the TNM tumor 
grading system, which describes the anatomical extent of the primary tumor (T stage), the regional 
lymph nodes (N stage), and the presence or absence of distant metastases (M stage) (American 
Joint Committee on Cancer [AJCC], Appendix 1 and Appendix 2). 
The focus of this protocol is on cancer of the oral cavity, selected for study in part because of the 
limitations of currently available therapies. In addition, there is evidence that the impact of the 
immune system upon HNSCC differs by tumor site [Rapidis, 2009]. Thus, in order to maximize 
the ability to detect benefit conferred by immune modulation, i.e. the IRX-2 Regimen, a 
homogenous patient population with respect to site and standard treatment modality is required. In 
addition, relatively few new therapeutic approaches directed to cancer of oral cavity are being 
investigated. 
1.1.3 
Rationale for Inclusion of Stage II Patients  
One-third to more than 50% of patients with clinical Stage II disease (i.e. node negative) are found 
upon pathological examination of resected lymph nodes to have nodal involvement and thus will 
be “upstaged” to Stage III [Ross, 2002; Sparano, 2004; O-Charoenrat, 2003]. Nodal size alone is 
an inaccurate predictor of nodal metastases, confirming the challenge of identifying pathological 
Stage III patients based on clinical staging [Alkureishi, 2007]. Seventy-two of 243 patients (30%) 
with clinical T1 or T2 N0 (Stages I or II) oral cancer were found to have pathological involvement 
of electively resected nodes, i.e. were upstaged to pathological Stage III [D'Cruz, 2015 and 
Supplemental Appendix, Table S4]. Patients with Stage III oral cavity cancer clearly have a worse 
prognosis for both recurrence and survival when compared to Stage I patients (Hazard Ratio for 
survival = 2.1-2.2), but it is clear that Stage II patients also have a poorer prognosis than do Stage 
I patients (Hazard Ratio for survival = 1.3) [Leoncini, 2015; Kreppel, 2011; Groome, 2001]. It is 
important to emphasize, however, that the above data are based on the pathological staging of 
patients, not on their pre-operative, clinical stage. Thus the Stage II Hazard Ratios for survival 
would be even greater if the above data were based on clinical, rather than pathological stage. 


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Subjects entered on this trial will be entered on study and randomized based upon their clinical 
stage, not their pathological stage. The randomization methodology will account for the major 
prognostic factors for HNSCC of the oral cavity, including T and N stage (and also study center; 
see Section 5.2.2 and Section 9). The prior Phase 1 and 2a trials of the IRX-2 Regimen 
(summarized in Section 1.3 below and in the Investigator’s Brochure) did not reveal significant 
safety concerns that would make it inappropriate to include earlier stage patients. Finally, as with 
other immune therapies, it may be that patients with relatively smaller tumor burdens are more 
likely to benefit from the IRX-2 Regimen, an observation that may be missed if such patients are 
not included in the trial. Thus patients with clinical Stage II oral cavity cancer will be included in 
this trial. 
1.1.4 
Immune Deficiency and Immunotherapy in HNSCC Patients 
The rationale for the pursuit of immunotherapy of HNSCC with the IRX-2 regimen stems from a 
considerable body of evidence, which indicates that immunologically competent cells are 
important host defense mechanisms. Many human cancers, however, including HNSCC, are 
associated with cellular immunodeficiency. Immunotherapies now in development for the 
treatment of HNSCC include nonspecific, systemic cell-mediated approaches, cytokine based 
immunotherapy (including delivery of granulocyte-macrophage colony stimulating factor [GM-
CSF], interleukin-2 [IL-2], interferon alpha [IFN-α], interferon gamma [IFN-γ], interleukin-12 
[IL-12], and IRX-2), tumor-associated antigens as therapeutic targets, monoclonal antibodies and 
cancer vaccines, either peptide/protein based, dendritic-cell based or nucleic acid based, and 
immune checkpoint inhibitors. Discussion of these many approaches is beyond the scope of this 
protocol Introduction but is presented in more detail in the Investigator’s Brochure (IB) and in 
several reviews [Rapidis, 2009; Freiser, 2013; Gildener-Leapman, 2013]. 
1.1.5 
The IRX-2 Regimen 
Dose/Regimen Rationale:  In the 1980s, investigators had shown that local administration of the 
cytokine interleukin-2 (IL-2) triggered lymphocytes from tumor-bearing mice to inhibit tumor 
growth [Forni, 1985] and that recurrent HNSCC could be treated with low doses of IL-2 injected 
perilymphatically [Cortesina, 1988]. Shortly thereafter, as discussed in Section 4.1.1 of the 
Investigator’s Brochure, cytokine mixtures now designated as IRX-2 were shown to result in 
stimulation of T cells in several animal models [Hadden, 1989]. One of the major T cell stimulating 
constituents found in IRX-2 is IL-2; however, in these model systems recombinant IL-2 (rIL-2) 
alone was unable to reproduce completely the proliferative effects seen with IRX-2. IRX-2 was 
also able to induce proliferation in murine T cell precursors from the spleens of athymic nude mice 
to a greater degree than rIL-2 [Hadden, 1989]. IRX-2 administered in vivo augmented proliferation 
of T cells in nude mice and in a murine model of immunodeficiency using hydrocortisone-treated 
aged mice, IRX-2 was able to restore thymic function and T cell numbers. IRX-2 treatment 
increased the recovery of spleen and thymus weights and cellularity with a corresponding 
augmentation of proliferation and function of T lymphocytes [Hadden, 1992; Hadden, 1995b]. 
Recombinant IL2 was not able to duplicate this effect. These data suggested that cytokine 
components of IRX-2, in addition to IL-2, acted on T cell function and promoted T cell 
development and proliferation. These functional effects of IRX-2 on T cells led the scientific 
founder of IRX Therapeutics, Dr. Hadden, to hypothesize that IRX-2 might be therapeutically 
relevant for immune restoration in immune deficient subjects [Hadden, 1995a].  


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The IRX-2 biologic differs from other types of cytokine therapy in the following:  
• physiologic rather than pharmacologic doses of the cytokines are administered;  
• administration is by subcutaneous injection in the perilymphatic areas rather than 
intratumoral or intravenous injection; and  
• product manufacture uses activated lymphocytes rather than recombinant DNA 
technology in order to simulate endogenous cytokine levels from native activated cells 
The route of administration takes advantage of the normal afferent and efferent pathways of lymph 
node activation. Normally, lymphatics drain from an area of interest, such as a tumor bed, and 
antigens and other factors associated with disease migrate through the lymphatics to the regional 
nodes. At the regional nodes, antigen presenting (dendritic) cells are responsible for securing and 
processing these disease-related antigens and presenting them to T cells, with resultant 
proliferation of activated, antigen-specific T cells. By administering IRX-2 locally, rather than 
systemically, DCs and T cells are activated directly to proliferate and become cytotoxic 
lymphocytes. Additionally, by localized rather than intravenous administration, lower systemic 
drug levels are likely, leading to less systemic toxicity. 
The major component of the IRX-2 Regimen is the cytokine mixture IRX-2 administered as above, 
but in a series of empiric studies, Dr. Hadden and colleagues added additional components, 
cyclophosphamide, indomethacin and multivitamins with zinc, for reasons summarized in Section 
1.1.8 below and in several publications [Hadden, 1994; Verastegui, 1997; Barrera, 2000]. 
Omeprazole was subsequently added as a supportive medication to decrease the incidence and 
severity of gastritis induced by the indomethacin. After the manufacturing of IRX-2 was 
standardized per a US IND (# 11,137); (see Section 1.1.6 below and the Investigator’s Brochure), 
a Phase 1 trial was performed in the United States and is summarized below in Section 1.3.1 and 
in more detail in the Investigator’s Brochure. This study was followed by a Phase 2a neoadjuvant 
trial of the same IRX-2 regimen in 27 subjects with resectable HNSCC as summarized below in 
Section 1.3.2 and in more detail in the Investigator’s Brochure. Thus, the doses and components 
of the IRX-2 Regimen to be studied in the current trial are based in part on preclinical data of IL-
2 and IRX-2 in preclinical models, ancillary data that led to the addition of the non-cytokine 
components of the IRX-2 Regimen, the early clinical experience with the IRX-2 Regimen in the 
1990s and finally, the current experience with this regimen in the Phase 1 and 2a trials performed 
in the United States indicating encouraging safety, immunological and survival results. 
The concept that subjects with HNSCC might benefit from immune stimulation led to the 
development of the IRX-2 regimen, consisting of the cell-derived biologic IRX-2 that contains 
multiple cytokines, cyclophosphamide, indomethacin, and zinc (administered as a multivitamin 
preparation containing zinc). These four components are administered as a regimen consisting of 
an intravenous (IV) infusion of low-dose cyclophosphamide on Day 1, followed by oral 
indomethacin and oral zinc- containing multivitamins daily for 21 days, and IRX-2 administered 
as two subcutaneous injections per day for ten days, as outlined in the Synopsis and below in Table 
1, Section 4.2. Omeprazole, a proton pump inhibitor, is given concurrently in accordance with its 
licensed dose and administration, to improve tolerance of the indomethacin. This IRX-2 Regimen 
has been previously studied in Phase 1 and 2a studies that are described below in Section 1.3 


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Booster Regimen†:  This study will also investigate the benefit of an IRX-2 Booster. It is a 10-
day post-operative regimen of cyclophosphamide on Day 1, indomethacin, zinc-containing 
multivitamins and omeprazole on Days 1-10 and subcutaneous IRX-2 injections in bilateral deltoid 
regions for 5 days between Days 4 and 10. The rationale for the Booster Regimen is to continue to 
provide a cytokine environment that will further stimulate T cells. We speculate that immune 
activation will be promoted in nodal tissue and this will further expand T cells that have already 
been primed to antigens found in the tumor. It is well established that immune responses, including 
cellular immune responses, are enhanced by continued stimulation. An abbreviated IRX-2 regimen 
is to be utilized for the Booster Regimen, since a shorter course of therapy every 3 months will be 
less burdensome to patients and thus likely will result in greater compliance. In addition, pre-
clinical data suggest that a 5-day course of IRX-2 is comparable to a 10-day course for 
enhancement of cellular responses to tumor-associated antigens [Naylor, 2010].  
1.1.6 
Manufacture and Composition of IRX-2 
IRX-2 is a primary cell-derived biologic with multiple active cytokine components produced under 
pharmaceutical standards as discussed in more detail in the IB. Briefly, human leukocytes (“buffy 
coats”) pooled from multiple donors are stimulated with phytohemagglutinin and ciprofloxacin. 
Subsequently, the phytohemagglutinin, ciprofloxacin and all cellular elements are removed or 
significantly reduced, and the cell-free supernatant is filter sterilized, nanofiltered to clear viral 
particles, vialed, and frozen as IRX-2. 
IL-2 is the major cytokine in IRX-2, followed by IFN-, TNF-α, and interleukin 1 beta (IL-1). 
These cytokines when studied individually enhance cell-mediated immunity via several different 
mechanisms discussed below and in the IB.  
1.1.7 
Mechanism of Action of IRX-2  
Recent in vitro studies have elucidated several potential mechanisms of action of IRX-2, and these 
various mechanisms of action need not be exclusive. IRX-2 treatment of human monocyte-derived 
dendritic cells results in changes consistent with the development of mature activated dendritic 
cells. Specifically, IRX-2 increased the percentage of cells expressing CD83 and CCR7, markers 
for dendritic cell maturation and migration and increased the expression of multiple markers that 
are critical mediators of T cell activation [Egan, 2007]. Similar results were obtained in a later 
study in cells obtained from patients with HNSCC [Schilling, 2013]. Also, in an in vitro study of 
peripheral blood mononuclear cells obtained from patients with HNSSC, IRX-2 up-regulated 
cytotoxicity of NK cells and did so more effectively than IL-2 [Schilling, 2012]. 
IRX-2 can also protect T cells from activation induced cell death by reversing microvesicle 
induced inhibition of the PI3K/Akt pathway and correcting the imbalance of pro- versus anti-
apoptotic proteins induced by tumor-derived microvesicles [Czystowska, 2009; Czystowska 
2011]. IRX-2 was superior to recombinant IL-7 and IL-15 in protecting T cells from tumor-induced 
apoptosis. The presence of IRX-2 in a tumor microenvironment model promoted the induction and 
expansion of IFN-+T-bet+ Teff and significantly decreased the induction of inducible IL-10+TGF-
β+ Treg. The responsible mechanism involved IFN-+-driven T cell polarization towards Teff and 
suppression of Treg differentiation [Schilling 2012]. In the Phase 2a study in patients with HNSSC 
(described below in Section 1.3.1), IRX-2 mediated reductions in circulating B and NKT cell 
numbers, suggesting redistribution of these cells to tissues [Whiteside 2012]. A decrease in naïve 


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T cells was also noted, suggesting their upregulation to memory T cells, while unchanged numbers 
of Tregs (suppressor T cells) after IRX-2 therapy indicated that IRX-2 does not expand this 
compartment, potentially benefiting anti-tumor immune responses [Whiteside, 2012].  
Finally, IRX-2 has been shown to induce enhanced T cell responses when administered with tumor 
antigen vaccines, raising the possibility that IRX-2 treatment in patients with HNSCC enhances 
endogenous antigen-specific T cell responses to the tumor [Naylor, 2010]. 
1.1.8 
Rationale for the Components of the IRX-2 Regimen 
The rationale for the components of the IRX-2 regimen is outlined below. 
Cyclophosphamide:  One mechanism for reversal of anergy and reversal of suppression of immune 
responses in subjects with malignancy by adoptive immunotherapy may be related to inhibition of 
regulatory T cell function [North, 1982; North, 1984]. Evidence indicates that cyclophosphamide 
inhibits Treg number and/or function [Emens, 2005]. Thus many clinical trials that involve 
immunotherapy or attempt to stimulate immune response to tumor antigens have employed low 
dose cyclophosphamide (300 mg/m2) as a component of the treatment regimen. This 
immunomodulatory dose is less than one-third of a typical anti-cancer dose and is intended to 
enhance the development of cell-mediated immunity by providing contrasuppression of tumor-
associated immune suppression (to reduce the number and function of regulatory T cells, i.e. Treg) 
[Berd, 1982; Machiels, 2001]. 
Pathways of local immune tolerance, escape mechanisms active within the tumor 
microenvironment and superimposed potent systemic mechanisms of immune tolerance have been 
reviewed [Emens, 2005] and are discussed in more detail in the Investigator’s Brochure (Section 
3.5.1). The use of cytotoxic chemotherapy in doses and schedules designed to abrogate specific 
mechanisms of immune tolerance in order to release the full potential of an antitumor immune 
response is discussed. Specifically, cyclophosphamide may be used to prime the immune system 
by promoting the differentiation of CD4+ T helper cells and by abrogating the suppressive 
influence of CD4+CD25+ T regulatory (Treg) cells. In the absence of Treg influence, high-avidity 
CD8+ T cells are recruited to an antigen-specific immune response. Cyclophosphamide also 
facilitates the establishment of memory CD8+ T cells. Thus inclusion of cyclophosphamide in 
combination trials with other immune-modulatory agents is supported by both pre-clinical and 
clinical data as reviewed in more detail by Emens (2005) and in the Investigator’s Brochure. 
Indomethacin:  Indomethacin, a nonselective COX-1/COX-2 inhibitor, is a potent inhibitor of 
prostaglandin synthesis and may reverse the immunosuppression induced by prostaglandin 
[Lapointe, 1992; Hadden, 1994]. Numerous experimental, epidemiologic, and clinical studies 
suggest that non-steroidal anti-inflammatory drugs, including indomethacin, suppress 
cyclooxygenase and have promise as anticancer agents, particularly for chemoprevention of and 
as adjuvant therapy in patients with cancer [Thun, 2002; Investigator’s Brochure]. 
Zinc with multivitamins:  Subclinical zinc deficiency is common in subjects with HNSCC, perhaps 
related to a history of alcohol consumption [Brookes, 1981]. The importance of zinc in cellular 
immunity has been described and several reviews are available [Good, 1979; Keen, 1990; Blewett, 
2012; Haase, 2014]. Alcohol consumption is frequently associated with nutritional deficiency, 
which can also result in impaired immune response [Słotwińska, 2014; Bianchini, 2012; 
Wintergerst, 2007]. Thus, based on these observations and the lack of any contraindication to their 
use, zinc-containing multivitamins have been added to the IRX-2 regimen. 


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Omeprazole:  Omeprazole, a proton pump inhibitor, is active at preventing indomethacin-induced 
gastritis. It is administered with the IRX-2 regimen to decrease the likelihood of indomethacin-
induced gastritis. (An alternative, therapeutically equivalent proton pump inhibitor may be 
substituted for omeprazole.) 
1.1.9 
Delivery of IRX-2 
The route of administration of IRX-2 takes advantage of the normal afferent and efferent pathways 
of lymph node activation. Normally, lymphatics drain from an area of disease, such as a tumor 
bed, and antigens and other factors associated with disease migrate in the lymphatics to the regional 
nodes. By presenting the cytokine-containing biologic in the area of the tumor-draining lymph 
nodes rather than systemically, there is an opportunity to mobilize antigen presenting cells and 
enhance dendritic cell function as well as directly activate T cells to proliferate and become 
cytotoxic lymphocytes. Additionally, subcutaneous administration may be less toxic since the 
systemic cytokine drug concentration is much lower. 
The Booster Regimen† is also designed to take advantage of the normal afferent and efferent 
pathways of lymph node activation discussed above. Given that the most common recurrences of 
oral cancer are local or in the thorax, the IRX-2 injections in the Booster Regimen† will be given 
by subcutaneous injection in bilateral deltoid regions, thereby being administered regionally but 
avoiding those areas most likely to be affected by surgery or post-operative radiation. 
1.2 
Nonclinical Studies with the IRX-2 Regimen 
Nonclinical studies have demonstrated an effect of IRX-2 on T cells in animal models as well as 
in cellular assays. Details of these studies are provided in the IB. 
1.3 
Clinical Experience with the IRX-2 Regimen in Subjects with HNSCC 
1.3.1 
Phase 1 Trial 
IRX 2 2004-B was a multicenter, Phase 1 trial in subjects with HNSCC designed to evaluate the 
clinical and laboratory safety and tolerability of the IRX-2 regimen. Results of the study are 
presented in the IB and have been published [Freeman, 2010]. The results indicate that the IRX-2 
regimen was well tolerated in subjects with advanced stage HSNCC who had progressed after 
surgery and/or radiation therapy. The reported toxicities were acceptable overall and did not 
preclude proceeding to additional trials. 
1.3.2 
Phase 2 Trial 
1.3.2.1 Study Design and Patient Demographics 
IRX-2 2005-A was a multi-center trial entitled “A Phase 2, Open-label Trial of the Safety and 
Biological Effect of Pre-operative Subcutaneous IRX-2 (with Cyclophosphamide, Indomethacin, 
and Zinc) in Subjects with Resectable Cancer of the Head and Neck.”  Results of the study are 
presented in the IB and have been published [Wolf, 2011; Berinstein, 2012; Whiteside, 2012] and 
are also summarized here.  
The study objectives were to determine the safety of the IRX-2 regimen when used as neoadjuvant 
(preoperative) therapy in a multi-center trial and to evaluate clinical, pathological, and 
radiographic tumor response and disease-free survival (DFS) and overall survival (OS). Of the 27 


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subjects, 15 had oral cavity cancer, 8 had oropharyngeal cancer, 1 had hypopharyngeal cancer, and 
3 had laryngeal cancer.  
1.3.2.2 Clinical Results 
1.3.2.2.1 
Radiographic changes: 
Changes in tumor size between baseline and immediately pre-operative, i.e. after the IRX-2 
regimen, measurements were evaluable in 23 subjects. Based on measurement of the longest single 
tumor diameter, tumor growth or shrinkage was as follows: 4 subjects had -20% to <-10% change, 
7 subjects had -10% to <0% change, 9 subjects had 0% to <10% change, 1 subject had 10% to 
<20% change and 2 subjects had ≥30% change in the target lesions [Wolf, 2011]. Review of the 
radiologic findings in relation to the pathology finding in the resection specimens, established that 
lymph node enlargement due to reactive hyperplasia could not be distinguished from enlargement 
related to tumor growth based on computed tomography (CT) or magnetic resonance imaging 
(MRI) scans [Wolf, 2011]. 
One subject underwent a fluorodeoxyglucose positron emission tomography (FDG-PET) CT scan 
at baseline and at completion of the IRX-2 regimen. Elevated glycolytic activity was observed in 
2 lymph nodes and in the primary tumor on the baseline PET scan. At the completion of the IRX-2 
regimen, there was a 75% decrease in glycolytic activity in these lesions [Wolf, 2011]. 
1.3.2.2.2 
Disease-free and Overall Survival: 
After 5 years of follow-up, 7 of the 27 subjects enrolled in this study relapsed, 3 at the primary 
site, 2 in the neck and 2 with distant metastases. Five subjects died of other causes. DFS at 1, 2 
and 3 years respectively was 72%, 64% and 62%; median DFS has not been reached. OS at 1, 2 
and 3 years respectively was 92%, 73%, and 69%; median OS has not been reached. These results 
for both DFS and OS appeared to be slightly superior to those observed in a comparable group of 
81 historical controls, treated at the University of Michigan and matched for baseline 
characteristics [G. Wolf, personal data]. 
1.3.2.3 Safety Results 
The IRX-2 regimen was tolerated with minimal toxicity. Compliance was excellent; all subjects 
completed the regimen and there were no unplanned delays in surgery as a result of the 
immunotherapy regimen. There were no reports from investigators of any unanticipated or unusual 
delays or difficulties in performing the planned resections or reconstructions or during the 
postoperative recovery. Twenty-six subjects underwent surgical resection, 9 patients received 
post-operative radiation therapy and 10 subjects received post-operative chemoradiation.  
The most common adverse events (AEs) were headache (30%), injection site pain (22%), nausea 
22%), constipation (15%), dizziness (15%), fatigue (11%), aspiration pneumonia (11%), anemia 
(11%) and myalgia (7%). All were grade 1-2 except for the aspiration pneumonias (one Grade 3, 
one Grade 4) and all resolved without sequelae. There were only minor (grade 1) alterations in 
post-treatment laboratory values. Eight serious adverse events (SAEs) in 7 subjects were reported 
during treatment and the 30-day post-operative period: aspiration pneumonia (n = 3), respiratory 
tract infection, asthma exacerbation, wound infection, neck abscess and alcohol withdrawal (n = 1 
each); only the postoperative wound infection was considered related to the study treatment [Wolf, 
2011]. During treatment, several subjects noted decreased pain or improved swallowing and no 
significant progressive symptoms were noted.  


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1.3.2.4 Immunologic Results 
Pretreatment tumor biopsies and the tumor surgical specimens from 25 patients were characterized 
by three pathologists for lymphocyte infiltration, necrosis and fibrosis using both hematoxylin and 
eosin stains and immunohistochemistry [Berinstein, 2012]. Kaplan-Meier estimates of overall 
survival are displayed in Figure 1 as a function of high and low lymphocyte infiltration in the 
surgical specimens after the IRX-2 immunotherapy. Eighteen subjects were in the better survival 
group and 7 were in the inferior survival group; the survival curves are significantly different (p 
<0.05) [Berinstein, 2012]. 
 
Figure 1 
Overall Survival by High and Low Lymphocyte Infiltration in the Surgical 
Resection Specimen (Study IRX-2 2005-A) 
 
 
When lymphocyte infiltration in the pretreatment biopsies was compared to that in the resected 
surgical specimen, increases in lymphocyte infiltration were seen as shown in Figure 2 (change in 
mean lymphocyte infiltration from the biopsy to the surgical specimen is shown on the y-axis) 
[Berinstein, 2012]. 
 


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Figure 2 
Lymphocyte Infiltration (Study IRX-2 2005-A) 
 
 
In addition, subjects in whom the greatest increase in tumor lymphocyte infiltration from biopsy 
to surgery (n=14) was observed had a trend toward superior survival compared to subjects in 
whom no or more limited change was observed (n=11) as shown in  
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3 (p = 0.10) (IRX Therapeutics, unpublished observations). 
 
 
 


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Figure 3 
Overall Survival by Change in Lymphocyte Infiltration from Biopsy to 
Resection Specimen (Study IRX-2 2005-A) 
 
Peripheral blood lymphocyte subsets also were monitored pre- and post-treatment with the IRX-2 
regimen to evaluate changes induced by the IRX-2 regimen (summarized in Section 1.1.7 above 
and in the IB). The IRX-2 regimen-mediated reductions in B and NKT cell numbers in the blood 
suggested a redistribution of these cells to tissues while the unchanged numbers of Tregs after IRX-2 
therapy indicated that IRX-2 does not expand this compartment, potentially benefiting anti-tumor 
immune responses [Whiteside, 2012].  
1.3.2.5 Time to Surgery 
Among the 27 subjects in this trial, the mean time from diagnostic biopsy to surgical resection was 
37 (range 22-63) days. Only one subject (4%) was operated upon >60 days from the date of 


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diagnostic biopsy. In 81 contemporary control patients treated at the University of Michigan 
matched to the 27 Phase 2 study patients, controlling for age, sex, tumor site and tumor stage (3:1 
match), the mean time from diagnostic biopsy to surgical resection was 24 (range 5-115) days and 
5 control patients (6%) underwent surgery >60 days from date of diagnosis (G. Wolf, unpublished 
data). Thus the 21 day neoadjuvant IRX-2 Regimen resulted in a prolongation of the time from 
biopsy to surgery of only approximately 13 days when compared to University of Michigan 
controls and the percent of patients with a time of >60 days was comparable. The IRX Medical 
Advisory Board considered such delay to be acceptable. 
Among the 27 subjects in this Phase 2 trial, the mean time from the date of informed consent to 
cyclophosphamide dose was 6.6 +5.3 (range 1-23, median 4.0) days. The mean time from the 
cyclophosphamide dose to surgery was 24 +3 days (range 19-31, median 25 days). Overall, the 
mean time from informed consent to surgery in this study was 31 (range 22-47, median 32) days 
(IRX Therapeutics, unpublished observations). Also, there were no unplanned delays in surgery 
as a result of the immunotherapy regimen. Thus, the requirement of proceeding to surgery within 
35 days following randomization is consistent with our prior experience. 


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2 
STUDY OBJECTIVES  
The purpose of the study is to evaluate neoadjuvant and adjuvant† IRX-2 therapy (Regimen 1) in 
a randomized setting compared to a regimen which does not include IRX-2 (Regimen 2). 
2.1 
Primary Objective 
The primary objective is to determine if the event-free survival (EFS, defined in Section 6.1.1) of 
subjects treated with Regimen 1 is longer than for subjects treated with Regimen 2. 
2.2 
Secondary Objectives 
Secondary objectives are: 
1. to determine if OS of subjects treated with Regimen 1 is longer than for subjects treated 
with Regimen 2 
2. to compare the safety of each Regimen 
3. to compare the feasibility of each Booster Regimen† 
2.3 
Exploratory Objectives 
To determine and compare between the Regimens:  
1. changes in tumor size from baseline to surgery measured by CT scans (MRI also 
acceptable, so long as the same modality is used for baseline and pre-surgery scans)  
2. changes from baseline to surgery in functional imaging as estimated by PET scan  
3. lymphocyte infiltrates in the pre-treatment tumor biopsy, the surgical specimen and 
changes between these two samples. These data will be analyzed to seek any baseline 
characteristics that are correlated with differences in outcome between the Regimens  
4. surgical pathology, including tumor characteristics (depth of invasion, perineural invasion, 
pattern of invasion, extent of necrosis), tumor margins and lymph node involvement 
5. prognostic and predictive factors and clinical-pathologic-immunologic correlates, 
including, for example, nutritional status (body mass index, albumin), absolute lymphocyte 
count, lymphocyte subsets and histological differences in the surgical specimen, gene 
expression profiles with EFS, recurrence, second primary tumors, and patterns of disease 
recurrence 
6. HPV status (p16 protein expression) and any relationship between tumor baseline p16 
protein expression and differences in outcome between the Regimens 
7. the peripheral T cell receptor profile prior to and post treatment during the first year of the 
trial 
8. RNA expression profiling of immune-inflammatory markers 


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3 
INVESTIGATIONAL PLAN 
3.1 
Study Design  
This is a prospectively randomized, open-label, multi-center, multi-national, Phase 2b clinical trial 
intended for patients with Stage II, III or IVA untreated SCC of the oral cavity who are candidates 
for resection with curative intent. Subjects will be randomized 2:1 in favor of Regimen 1 as 
described in Section 5.2.2.  
The interventions to be used for the subjects randomized to these arms are: 
• Regimen 1: Subjects will receive the neoadjuvant IRX-2 regimen prior to surgery, and then 
IRX-2 Booster Regimens† as clinically feasible every 3, 6, 9 and months 12 (-14 to +28 days)  
after surgical resection as detailed in Section 5.2.8 below.  
• Regimen 2: Subjects will receive the IRX-2 regimen minus the IRX-2 biologic prior to 
surgery, and the IRX-2 Booster Regimen† minus the IRX-2 biologic as clinically feasible 
every 3, 6, 9, and 12 months 12 (-14 to +28 days) after surgical resection as detailed in Section 
5.2.8 below.  
• All randomized subjects are to receive standard of care surgery and postoperative adjuvant 
radiation or chemoradiation therapy, as appropriate. These non-investigational, standard of 
care therapies and related evaluations and supportive care are reasonable and medically 
necessary for the clinical management of the subject. 
The flow chart presented in Figure 4 illustrates the study design of both arms. 
 
Figure 4 
Flow Chart of Study Design 
 
 
Randomization 
Investigational Arm 
(Regimen 1) 
Control Arm 
(Regimen 2) 
Surgery 
Postoperative 
adjuvant therapy 
and follow-up 
Booster Regimen 1† 
Surgery 
21-Day Regimen minus IRX-2 
21-Day IRX-2 Regimen  
Postoperative 
adjuvant therapy and 
follow-up 
Booster Regimen 2† 
minus IRX-2 


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3.1.1 
Rationale for Study Design 
The rationale for the study drug, IRX-2, has been discussed above in Sections 1.1.4-1.1.7, for the 
Booster Regimen† in Section 1.1.5 and for the other components of the IRX-2 regimen, 
cyclophosphamide, indomethacin, zinc with multivitamins and omeprazole, in Section 1.1.8. 
In this randomized open label Phase 2 study, one study arm will receive the complete IRX-2 
neoadjuvant and adjuvant booster regimens†. Many options for the therapy to be received by the 
control group were considered, ranging all the way from no therapy at all (go directly to surgery, 
the current standard of care in most institutions) to a double-blind study with placebo instead of 
IRX-2 injections. It was considered, however, that offering all patients the potential benefits of the 
components of the IRX-2 Regimen other than the IRX-2 injections would make the study more 
acceptable to both potential subjects and investigators. In addition, this design alleviates the 
difficulty of analysis of a study in which the time of the most important therapeutic intervention, 
i.e. surgical resection of the tumor, differs between the two study arms. The 2:1 randomization 
scheme was adopted to make the study more acceptable to both potential subjects and 
investigators. There was concern among potential study investigators that placebo injections would 
not be acceptable to many investigators or potential subjects. Thus a “middle ground” study design 
was chosen, i.e. the control arm is to receive all components of the IRX-2 regimen but no injections 
of study drug IRX-2, so the final analysis will focus primarily on the contribution of the 
investigational drug, IRX-2 to efficacy and safety. 
This design, with awareness of both subject and investigator of the treatment arm, does introduce 
some possibility of bias. This will be minimized by close monitoring of the study as discussed in 
the following Section. Also, OS an important secondary endpoint will be less subject to bias than 
the primary endpoint, EFS. 
3.1.2 
Rationale for Endpoints 
EFS and OS:  Overall survival is generally the preferred endpoint for the evaluation of anticancer 
medicinal products in humans. In HNSCC, however, recurrence is in itself a clinically devastating 
event, requiring additional therapy, which unfortunately is likely to be associated with significant 
adverse events and only limited clinical benefit. Recurrence and death are closely correlated since 
treatment of recurrent disease is usually not curative, i.e., while recurrent HNSCCs are often 
responsive to chemotherapy, only a modest effect on survival has been demonstrated. Thus, 
median survival after recurrence is only 3 to 9 months, emphasizing the need for improvements in 
the initial therapy of HNSCC. Data from several meta-analyses have revealed that in this disease, 
EFS should be considered an acceptable surrogate endpoint for OS [Michiels, 2009]. This 
approach is also consistent with European Medicines Agency (EMA) standards, i.e. “prolonged 
progression-free or disease-free survival (PFS/DFS) are relevant measures of patient benefit, but 
the magnitude of the treatment effect should be sufficiently large to outbalance toxicity and 
tolerability problems” (EMA/CHMP/205/95/Rev.4). Using EFS as the primary study endpoint, 
and OS as an important secondary endpoint, will also enable an early decision to be made regarding 
the design and initiation of a larger, Phase 3 registration trial.  
Safety of IRX-2:  No significant safety concerns have been recognized in prior Phase 1 and Phase 
2a clinical trials of the IRX-2 regimen. Nevertheless, both trials were relatively small trials without 
a comparator arm. Therefore, in this trial the safety of IRX-2 will be determined by comparison of 
AEs, surgical results, study discontinuation, etc., between the two study arms.  


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Feasibility of Booster Regimen†:  The IRX-2 Booster Regimen has not been previously studied in 
clinical trials. Since both Booster Regimens are of shorter duration than the neoadjuvant regimen 
no safety concerns are anticipated. Nevertheless, subjects receiving the Booster Regimens will be 
post-operative and many will also have received adjuvant radiation or chemoradiation. Thus, their 
ability to receive and tolerate even a shorter IRX-2 regimen will be specifically evaluated in this 
study (See Section 5.2.8). 
3.1.3 
Benefit/Risk Assessment and Study Monitoring 
Patients with Stage II-IVa SCC of the oral cavity face significant risks associated with their tumor, 
surgery, reconstruction, adjuvant radiation and chemotherapy as well as with frequently associated 
co-morbidities including smoking, alcohol, nutritional deficiency and immune suppression. This 
was seen in the prior study of the IRX-2 Regimen (see Section 1.3.2.3) and the IB), i.e. only one 
of eight SAEs, a post-operative wound infection, was considered possibly related to the study 
regimen. At this stage of development, the benefit of the IRX-2 regimen remains to be established, 
but given the rationale for the regimen and the prior experience, the potential benefit seems likely 
to exceed the associated risks, especially compared to the risks already faced by eligible patients, 
or, at the least, not to increase the risks already faced by eligible patients.  
One risk specifically considered in the design of this study, however, was whether trial participants 
would be exposed to any risk by delay in time to surgery. The results of the multicenter Phase 2a 
study that preceded and led to this trial are reassuring in this regard, i.e. 26 of the 27 patients 
received the surgery originally intended and there were no unplanned delays in surgery (see 
Section 1.3.2.5). 
Other subject safety issues (risks) will be assessed and, in so far as possible, mitigated by 
monitoring of the ongoing study by the Principal Investigator (see Sections 3.4 and 3.7.2), the 
Medical Monitors of the CRO and Sponsor (Section 3.7.1) and a DSMB (Section 3.8). The DSMB 
will consist of physicians and a statistician who are not otherwise involved in the trial and will 
specifically monitor the study for delay in definitive surgery (as described in Section 8.5 below), 
for adherence to protocol and international guidelines for adjuvant radiation and chemoradiation 
in each protocol arm and for the safety and feasibility of the Booster Regimens† in this study. At 
the discretion of the Sponsor an Interim Analysis (IA) may be preformed as specified in Protocol 
Section 9.5. 
3.1.4 
Estimated Duration of Study 
As discussed in more detail in Section 9, the number of EFS events required for the assessment of 
the primary endpoint is 51. The required number of deaths for the assessment of the OS endpoint 
is also 51. 
Protocol mandated follow-up will end 4 years after randomization of the last subject, i.e. in Q1 
2022. Subjects should be on site for all Year 1 and Year 2 follow up visits (i.e., Y1M3, Y1M6, 
Y1M9,  Y1M12, Y2M3, Y2M6, Y2M9 and Y2M12). Lab samples will be collected in Year 1 only 
(see Table 5 for required assessments). All follow up visits during Y3 and Y4 post-surgery will be 
performed via telephone calls to collect survival information. Subjects should receive yearly tumor 
imaging and be followed in the office per standard practice at each facility for physical 
examinations, etc. Any indication of progression or recurrence which is noted at a standard of care 
visit should be reported in the Recurrence case report form for this study.   


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3.2 
Selection of Study Population 
3.2.1 
Inclusion Criteria 
To be enrolled in the study, subjects must meet the following inclusion criteria. 
1. Pathologically confirmed clinical Stage II, III or IVA squamous cell cancer of the oral cavity 
(excluding lip). Subjects must be staged using AJCC Cancer Staging Manual Edition 7.0 
(Appendix 1 and Appendix 2). 
2. Disease is surgically resectable with curative intent   
3. Hematological function: hemoglobin >9 g/dL; lymphocyte count >0.50 × 109/L; neutrophil 
count >1.50 × 109/L; platelet count >100 × 109/L 
4. Hepatic function: serum albumin >3.0 g/dL; aspartate aminotransferase (AST/SGOT) and 
alanine aminotransferase (ALT/SGPT) <3× the upper limits of normal (ULN); alkaline 
phosphatase <2× ULN 
5. Prothrombin time (PT) and partial thromboplastin time (PTT)  <1.4× ULN 
6. Calculated creatinine clearance >50 mL/min (Appendix 4) 
7. At least 18 years of age 
8. Willing and able to give informed consent and adhere to protocol therapy 
9. Karnofsky performance status (KPS) is 70% 
10. From the date of screening until 1 year after the last dose of study regimen, females of 
childbearing potential (not surgically sterile or less than 12 months post-menopausal) must be 
able and willing to use:  
-          One highly effective form of pregnancy prevention defined as:  
o   male condoms with spermicide, 
o   intrauterine device (IUD) (hormonal or nonhormonal),  
o   intrauterine hormone-releasing system (IUS), 
o   oral contraception  
o   or complete abstinence (defined as complete avoidance of heterosexual 
intercourse). Subjects who choose complete abstinence must continue to have 
pregnancy tests throughout the study. Alternate methods of contraception must be 
discussed in the event the subject chooses to forego complete abstinence. 
-          Or two less effective methods of pregnancy prevention defined as: 
o   male condoms without spermicide, 
o   diaphragm with spermicide, 
o   cervical cap with spermicide, 
o   vaginal sponge, 
o   female condom [not to be used with a male condom] 
Males with a partner of childbearing potential must use condoms with spermicide from the date 
of screening to 1 year after their last dose of study regimen. 
11. Negative urine/serum pregnancy test (females only), if applicable 


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3.2.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Prior surgery, radiation therapy, or chemotherapy other than biopsy or emergency procedure 
required for supportive care of this oral cavity cancer. 
2. Any medical contraindications or previous therapy that would preclude treatment with either 
IRX-2 Regimen 1 or 2 or the surgery, reconstruction or adjuvant therapy required to treat the 
oral tumor appropriately.  
a. Live vaccines should ideally not be administered to any patients undergoing 
treatment with chemotherapy or immunotherapy, but if need be, they should be 
administered >4 months prior to the initiation of treatment or >4 months after the 
completion of all treatment.  
b. Inactivated vaccines should precede the initiation of any study regimen and/or 
standard adjuvant therapy by at least 2 weeks, but preferably 4 weeks or longer.  
3. Clinical status of either subject or tumor such that administration of 21 day neoadjuvant IRX-2 
Regimen 1 or 2 before surgery would be medically inappropriate.  
4. Tumor of the oropharynx 
5. Tumor involvement of the following sites or any of these signs or symptoms likely to be 
associated with T4b cancer: 
a. involvement of pterygopalatine fossa, maxillary sinus, or facial skin; 
b. gross extension of tumor to the skull base; 
c. pterygoid plate erosion; 
d. sphenoid bone or foramen ovale involvement; 
e. direct extension to involve prevertebral fascia; 
f. extension to superior nasopharynx or Eustachian tube; 
g. direct extension into the neck with involvement of the deep neck musculature (neck 
node fixation); 
h. suspected invasion (encasement) of the common or internal carotid arteries. 
Encasement will be assessed radiographically and will be defined as tumor 
surrounding the carotid artery 270o or greater; 
i. direct extension of neck disease to involve the external skin; 
j. direct extension to mediastinal structures; 
k. regional metastases to the supraclavicular neck (low level VB and IVB) 
6. Any investigational agent within the previous 30 days. 
7. Daily administration of systemic immunosuppressive therapy or corticosteroids (except in 
physiological doses for hormone deficiency) during the previous 30 days. 
8. Chronic anticoagulation, not including aspirin, but including heparins, warfarin, oral 
anticoagulation or other platelet function inhibitors, that can not, in the documented opinion of 
the investigator, safely be interrupted from at least 2 days prior to the initiation of the study 
regimen until after surgical resection of the tumor. 


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9. Symptomatic cardiopulmonary disease (including congestive heart failure and hypertension), 
coronary artery disease, serious arrhythmia or chronic lung disease. Patients with these 
conditions who are stable with relatively minor symptoms and who are appropriate candidates 
for surgical treatment of their tumor need not be excluded. 
10. Myocardial infarction within the last 3 months. 
11. Evidence of distant metastases (M1 disease) or other concurrent primary malignancy. 
12. Known infection with hepatitis B, hepatitis C, or HIV. 
13. Signs or symptoms of systemic  infection (use of antibiotics to treat superficial infection or 
contamination of tumor shall not, by itself, be considered evidence of infection). 
14. Clinically significant gastritis or peptic ulcer disease that would contraindicate the use of 
indomethacin. 
15. Stroke or other symptoms of cerebral vascular insufficiency within the last 3 months. 
16. Allergy to ciprofloxacin (or other quinolones), acetylsalicylic acid, or indomethacin. 
17. Previous diagnosis of invasive cancer from which the individual is NOT disease-free AND 
that has required treatment within the past 5 years, except for superficial skin, cervical cancer 
in-situ, well-differentiated thyroid or early stage prostate or bladder cancer (i.e., treatment with 
curative intent and long term disease-free expectations). 
18. Prior axillary dissection. 
19. Breastfeeding women. 
3.3 
Tumor Staging  
Initial tumor staging will be performed using National Comprehensive Cancer Network (NCCN) 
Surgical Guidelines prior to randomization and will be based on clinical and endoscopic criteria 
supplemented by thin section, high resolution CT or MRI of the neck and chest (inclusive of the 
adrenals). The TNM staging and stage grouping is based on American Joint Committee on Cancer 
(AJCC) clinical staging criteria Edition 7.0  (Appendix 1 and Appendix 2). 
All subjects must have pre-treatment imaging with thin-slice CT or MRI of the neck and chest 
with contrast as necessary to include assessment of lymph nodes, deep neck muscles, nasopharynx, 
retropharyngeal space, mandible, and skull base. Supplemental information obtained through CT 
or MRI imaging for staging of the neck will be based on axial scans using ≤5 mm slices. Contrast 
enhancement will be used unless there are contraindications to its use. Nodes identified will be 
considered positive for staging purposes if any of the following criteria are met: 
1. 
Size is >1.5 cm for one or more jugular digastric nodes; 
2. 
Evidence of central necrosis in a node; or 
3. 
Multiple nodes identified that each separately measure >1.0 cm. 
The clinical level of lymph nodes (Level I-VI) identified by CT or MRI imaging will be 
documented. Subjects with a N0 neck by clinical examination that have CT or MRI imaging 
evidence of regional lymphadenopathy will be considered N+ for the purposes of staging and 
inclusion in the study. 


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All subjects will undergo pre-treatment endoscopic evaluation of tumor extent that must include 
direct, indirect, or fiber-optic laryngoscopy, bidirectional tumor measurements and adequate tumor 
biopsy. 
PET scans will be obtained per institutional practice and for all those subjects to be assessed for 
Key Exploratory Endpoint #2, (changes from baseline to surgery in functional imaging).  
3.4 
Assessment of Surgical Resectability 
The head and neck surgeon must consider the disease to be resectable for cure in order for the 
subject to be eligible for the study. Clinical and radiographic assessments will be used to determine 
whether the tumor is unresectable at either the primary site or in the neck. Any uncertainty should 
be discussed via phone or email with the Study PI, Dr. Wolf. 
Ineligible subjects are those subjects for whom surgical excision is unlikely to result in negative 
margins including subjects with: 
1. 
involvement of pterygopalatine fossa, maxillary sinus, or facial skin; 
2. 
gross extension of tumor to the skull base (ie, T4b); 
3. 
pterygoid plate erosion; 
4. 
sphenoid bone or foramen ovale involvement; 
5. 
direct extension to involve prevertebral fascia; 
6. 
extension to superior nasopharynx or Eustachian tube; 
7. 
direct extension into the neck with involvement of the deep neck musculature (neck node 
fixation); 
8. 
suspected invasion (encasement) of the common or internal carotid arteries (T4b). 
Encasement will be assessed radiographically and will be defined as tumor surrounding the 
carotid artery 270° or greater; 
9. 
direct extension of disease to involve the external skin; 
10. direct extension to mediastinal structures; or 
11. regional metastases to the supraclavicular neck (low level VB and IV B). 
3.5 
 Termination of Study Treatment 
The investigator can stop the study treatment Regimen due to an allergic or hypersensitivity 
reaction to the study drug, an SAE or clinically significant AE or laboratory abnormality, 
withdrawal of consent or for protocol noncompliance. If a subject is discontinued from the study 
due to an AE or SAE, the investigator should notify the designated CRO within 24 hours of the 
event. Any clinically significant AEs or SAEs leading to premature termination of a study 
treatment regimen are to be followed until stability or resolution. 
Regardless of the reason for study termination, the investigator must complete the Study 
Disposition and Treatment Termination in the Case Report Form (CRF), specifying the reason. 
Subjects who discontinue study treatment should continue follow-up visits and be monitored for 
recurrence and survival, unless the subject specifically withdraws consent for follow-up.  


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NOTE:  Subjects may experience changes in primary tumor or regional lymph nodes during 
treatment with the IRX-2 regimen, including inflammation, necrosis, or change in 
consistency. These changes should not be mistaken for tumor progression prior to surgery. 
All treatment of all subjects will end after the last planned Booster Regimen†, approximately 12 
months after surgery. Subjects will be followed for protocol-specified follow-up for 4 years after 
randomization but in-person follow up visits only need to be performed during Year 1 and Year 2 
post-surgery (Y1M3, Y1M6, Y1M9, Y1M12, Y2M3, Y2M6, Y2M9, and Y2M12). Year 3-4 
follow-up visits should be performed via telephone calls to collect survival information (see also 
Section 5.2.9). During years 3-4, subjects should receive yearly tumor imaging and be followed in 
the office per standard practice at each facility for physical examinations, etc. Any indication of 
progression or recurrence which is noted at a standard of care visit should be reported in the 
Recurrence case report form for this study.  Subjects who withdraw prematurely from study-related 
treatment will be encouraged to continue protocol specified follow-up. Subjects who refuse 
protocol-specified follow-up will be encouraged to permit continued follow-up for survival. All 
randomized subjects will be analyzed and no subjects will be replaced. 
3.6 
Withdrawal of Consent 
Any subject may terminate participation in the study at any time but every effort should be made 
to continue with study evaluations for tumor recurrence and survival, even if a subject declines 
further study treatment. If a subject elects to discontinue study participation at any time for safety, 
medical or personal reasons, the investigator should make a reasonable effort to determine the 
reason for the subject’s withdrawal and document the reason on the CRFs. 
 
3.7 
Medical Monitoring 
3.7.1 
Medical Monitors 
Medical Monitors are physicians trained in the conduct of clinical trials who are available to the 
clinical investigators for discussion of questions regarding the inclusion/exclusion criteria and any 
other medical issues that may arise. Medical Monitors will be designated by the Sponsor, IRX 
Therapeutics.  
3.7.2 
Principal Investigator(s) 
The Study Principal Investigator or his designee should be contacted to discuss questions related 
to surgical resectability or operative details. 
Principal Investigator: 
Gregory T. Wolf, MD 
 
University of Michigan 
 
Otolaryngology Head and Neck Surgery 
 
1500 E. Medical Center Drive 
 
Ann Arbor, MI  48109 
 
Phone:  (734) 936-9178 
 
Facsimile:  (734) 936-9625 
 
Email: gregwolf@med.umich.edu  
    


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3.8 
Data Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will be established to monitor the conduct of the 
study as well as safety data. The DSMB will consist of physicians and a statistician who are not 
otherwise involved in the trial. The DSMB will meet via teleconference or in person over the 
course of the study and may also meet on an unscheduled basis if any unexpected safety concerns 
arise. The DSMB will monitor the study for delay in definitive surgery as described in Section 8.5. 
Detailed information regarding standard of care adjuvant therapy for subjects in each arm will be 
reviewed. Additional details of DSMB procedures and communication with Investigators and the 
Sponsor will be described in a separate Charter. 


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4 
STUDY TREATMENTS 
4.1 
Study Design and Randomization  
Subjects who meet all eligibility criteria will be randomized 2:1 to either Regimen 1 or Regimen 2 
and treated for 21 days prior to surgery and then postoperatively with a Booster Regimen† given 
every 3 months for 1 year (a total of 4 times as detailed in Section 5.2.8 below).  
• Regimen 1: IRX-2 Regimen with cyclophosphamide, indomethacin, zinc-containing 
multivitamins, omeprazole and IRX-2 as neoadjuvant and adjuvant† therapy as shown in 
Section 4.2. 
• Regimen 2: Regimen 1 with cyclophosphamide, indomethacin, zinc-containing 
multivitamins, omeprazole but without IRX-2 as neoadjuvant and adjuvant† therapy as 
shown in Section 4.3. 
4.2 
Regimen 1 
The Neoadjuvant IRX-2 Regimen is a 21-day pre-operative regimen of IV cyclophosphamide on 
Day 1, oral indomethacin, zinc-containing multivitamins and omeprazole on Days 1-21, and 
subcutaneous IRX-2 injections in bilateral mastoid insertion regions for 10 days, between Days 4 
and Day 21. The last injection must be at least 48 hours prior to surgery.  
In jurisdictions where approved, subjects may have a visiting nurse or other qualified medical 
personnel come to their homes to administer study drug injections. Other properly trained 
individuals may administer study drug for study subjects at mutually acceptable locations if 
approved by the Medical Monitor and the investigation site. If the nurse or other qualified medical 
personnel receives information about an AE, she/he will document the event and notify Study site 
personnel.  
4.2.1 
IRX-2 Booster Regimen† 
The IRX-2 Booster Regimen is a 10-day regimen, consisting of IV cyclophosphamide on Day 1, 
oral indomethacin, zinc-containing multivitamins and omeprazole on Days 1-10, and subcutaneous 
IRX-2 injections in bilateral deltoid regions for 5 days, between Days 4 and Day 10. Booster 
Regimens are to be administered as clinically feasible 3, 6, 9 and 12 months (-14 days to +28 days) 
after surgical resection as detailed in Section 5.2.8 below. Any Booster injection which cannot be 
given during the specified timeframe should be omitted and  the next scheduled Booster Regimen 
should be administered subsequently at the appropriate designated interval after surgical resection. 
Missed Booster regimens must not be given at a later date.  
The quarterly Booster Regimens must not be initiated until after completion and recovery from 
adjuvant radiation or chemoradiation as determined by the investigator. The investigator’s 
determination of adequate recovery should be based review of any ongoing adverse events, and 
the overall clinical status of the subject as determined by the Investigator. Any uncertainty should 
be discussed with the Medical Monitor. 
In jurisdictions where approved, subjects may have a visiting nurse or other qualified medical 
personnel come to their homes to administer any or all Booster study drug injections as described 


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above. Other properly trained individuals may administer study drug for study subjects at mutually 
acceptable locations if approved by the Medical Monitors and the investigation site PI.  
The Neoadjuvant and Booster Regimens† are shown in Table 1 and Table 2: respectively: 
 
Table 1: 
IRX-2 Neoadjuvant Regimen  
Agent 
Dose 
Route of 
Administration 
Treatment Days 
Cyclophosphamide 
300 mg/m2 
IV 
1 
IRX-2 
230 units daily 
(Bilateral 
injections of  
115 units) 
Subcutaneous at or 
near the mastoid 
insertion of right 
and left 
sternocleidomastoid 
muscles 
Any 10 days 
between Days 4 and 21*  
 
*Indomethacin 
25 mg TID 
Oral 
1-21 
**Zinc-containing 
multivitamins 
1 tablet 
containing 15-30 
mg of zinc 
Oral 
1-21 
**Omeprazole 
20 mg daily 
Oral 
1-21 
* The last IRX-2 injection and oral indomethacin must be at least 48 hours prior to surgery.  
  **Subjects should not make up the missed doses of these medications. See Section 4.4.4 for guidance on 
administration of all oral medications. 
 
Table 2 
IRX-2 Booster Regimen†  
Agent 
Dose 
Route of 
Administration 
Treatment Days 
Cyclophosphamide 
300 mg/m2 
IV 
1 dose on Day 1 every 3 
months for 1 year 
IRX-2 
230 units daily 
(Bilateral 
injections of 115 
units) 
Subcutaneous into 
bilateral deltoid 
areas 
Every 3 months  
Any 5 days between Days 4 
and 10 
*Indomethacin 
25 mg TID 
Oral 
Every 3 months Days 1-10 
*Zinc-containing 
multivitamins 
1 tablet 
containing 15-30 
mg of zinc 
Oral 
Every 3 months Days 1-10 
*Omeprazole 
20 mg daily 
Oral 
Every 3 months Days 1-10 
*Subjects should not make up the missed doses of these medications. See Section 4.4.4 for guidance on 
administration of all oral  medications. 


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4.3 
Regimen 2 
4.3.1 
Description of Regimen 2 
The Neoadjuvant Control Regimen is a 21-day pre-operative regimen of IV cyclophosphamide on 
Day 1 and oral indomethacin, zinc-containing multivitamins and omeprazole on Days 1-21 as 
shown in Table 3: 
The Control Booster Regimen† is a 10-day regimen consisting of IV cyclophosphamide on Day 1, 
oral indomethacin, zinc-containing multivitamins and omeprazole on Days 1-10, administered  as 
clinically feasible every 3, 6, 9 and 12 months (-14 days to + 28 days), after surgical resection as 
detailed in  Table 4 below. 
 
Table 3 
IRX-2 Neoadjuvant Control Regimen 
Agent 
Dose 
Route of 
Administration 
Treatment Days 
Cyclophosphamide 
300 mg/m2 
IV 
1 
*Indomethacin 
25 mg TID 
Oral 
1-21 
*Zinc-containing multivitamins 
1 tablet 
containing 15-30 
mg of zinc 
Oral 
1-21 
*Omeprazole 
20 mg daily 
Oral 
1-21 
* Subjects should not make up the missed doses of these medications. See Section 4.4.4 for guidance on 
administration of all oral medications. 
 
Table 4 
IRX-2 Booster Control Regimen† 
Agent 
Dose 
Route of 
Administration 
Treatment Days 
Cyclophosphamide 
300 mg/m2 
IV 
1 dose on Day 1 every 3 
months for 1 year 
*Indomethacin 
25 mg TID 
Oral 
Every 3 months Days 1-10 
*Zinc-containing 
multivitamins 
1 tablet 
containing 15-30 
mg of zinc 
Oral 
Every 3 months Days 1-10 
*Omeprazole 
20 mg daily 
Oral 
Every 3 months Days 1-10 
* Subjects should not make up the missed doses of these medications. See Section 4.4.4 for guidance on 
administration of all oral medications. 
 
 


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4.4 
Regimen Medications 
4.4.1 
IRX-2 
IRX-2 is supplied as a pale yellow, sterile liquid for subcutaneous injection in 2.0 mL single-dose 
vials. All immediate study supply containers will be appropriately labeled to identify study 
number, kit numbers, lot number, and product identity. Kit and lot numbers of IRX-2 will be 
recorded in the CRF. Study syringes for subcutaneous IRX-2 administration will be disposed of in 
accordance with biosafety procedures. IRX-2 injections must be discontinued at least 48 hours 
prior to surgery. 
4.4.2 
IRX-2 Storage 
IRX-2 must be stored in a secure area and maintained under labeled storage conditions at a range 
of −15oC to –50o C. 
4.4.3 
Supply of Other Medications 
Cyclophosphamide will be either purchased by the pharmacy of the study site and reimbursed by 
the Sponsor or directly supplied by the Sponsor. The Sponsor will supply indomethacin, zinc 
(with multivitamins) and omeprazole to study institutions. (An alternative, therapeutically 
equivalent proton pump inhibitor may be substituted by the subject or investigator for 
omeprazole.)  
4.4.4 
Administration of  Other Medications  
Intravenous administration of cyclophosphamide preferably should be administered into the tubing 
of an open i.v. infusion. Care should be taken that extravasation does not take place, however, 
should it occur, treat per manufacturer instructions.  
A suggested antiemetic regimen would include a serotonin (5-HT3) antagonist and lorazepam. 
Corticosteroids are not needed because this dose of cyclophosphamide is associated with minimal 
nausea. Corticosteroid administration also may inhibit the intended stimulation of an anti-tumor 
immune response.  
Administration of all oral medications (indomethacin, zinc containing multivitamins and 
omeprazole) should be limited to 21 days in the Neoadjuvant Regimen and 10 days in the Booster 
regimens†, i.e. medication days should not be added to make up for missed days of medications, 
although omeprazole may be continued as clinically indicated. 
Indomethacin and IRX-2 injections must be discontinued at least 48 hours prior to surgery. 
For further guidance on the administration of all other drugs see the appropriate SmPC/Package 
Inserts. 
 


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4.5 
Method of Assigning Subject Numbers 
After a subject has signed the informed consent form, the investigator will use an integrated web 
and telephone interactive recognition system (IxRS) to have a subject number assigned to that 
subject. Subjects who withdraw from the study after being assigned a subject number will retain 
that number. 
4.6 
Treatment Compliance  
The investigator, study personnel or other trained individuals will administer IRX-2 injections to 
ensure treatment compliance. Subjects should be asked each day that they are seen about 
compliance with oral medications and compliance (or lack thereof) documented in the clinical 
record. 
4.7 
Prohibited, Prior and Concomitant Treatments 
Subjects in both Regimen 1 and Regimen 2, from randomization to surgery and during Booster 
Regimens†, should not take aspirin (except for low-dose aspirin, e.g. 81 mg), corticosteroids or 
other non-prescribed, non-steroidal anti-inflammatory agents. Use of corticosteroids or other 
immunosuppressive medications after surgery is discouraged and should be minimized. 
Information on all other concomitant prescribed medications, recognized over-the-counter 
medications, or any changes in medications during the study from randomization to surgery will 
be collected. Thereafter, only information on medications given to treat a reported AE or SAE, or 
as anti-tumor therapy, will be collected. 
 
5 
STUDY PROCEDURES AND SCHEDULE 
5.1 
Study Schedule 
The Schedule of Study Procedures for both Regimen 1 and Regimen 2 is outlined in Table 5. All 
protocol deviations will be captured and reported. 
 
 


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Table 5 
Schedule of Events 
Study Procedure 
Screeninga 
Treatment Period 
Assessments 
Booster Regimens† and Follow-up Assessmentsd,e 
Year 1c 
Year 2 
Year 3 
(Phone 
calls) 
Year 4 
(Phone 
calls) 
Recurrencee, 
new tumore, or 
early 
termination 
Study Day 
-21 to -1 
DAY 1 
Day 15-18 
(+ 3 days;or 
last IRX-2 
dose) 
Days 1-5 
Prior to 
Surgery 
Dayb 
25-30 
3, 6, 9, and 
12 months 
post-surgery 
Q 3 
mont
h 
Q 6 
month 
Q 6 
month 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
 
 
 
 Medical history 
X 
 
 
 
 
 
 
 
 
 
Alcohol and Tobacco 
history 
X 
 
 
 
 
 
 
 
 
 
Endoscopy/Tumor 
staging 
X 
 
 
 
 
 
 
 
 
X 
Assessment of 
Surgical Resect ability 
Tumor Stage 
X 
 
 
 
 
 
 
 
 
 
Randomization 
X 
After Screening, Within  
7 days prior to Day 1 
 
 
 
 
 
 
 
 
Surgical Resectionb 
 
 
 
 
Xb 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
X 
Head/Neck Examd 
X 
X 
X 
X 
 
X 
X 
 
 
X 
Brief physical  Exam 
 
X  
 
X 
 
X 
X 
 
 
 


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Study Procedure 
Screeninga 
Treatment Period 
Assessments 
Booster Regimens† and Follow-up Assessmentsd,e 
Year 1c 
Year 2 
Year 3 
(Phone 
calls) 
Year 4 
(Phone 
calls) 
Recurrencee, 
new tumore, or 
early 
termination 
Study Day 
-21 to -1 
DAY 1 
Day 15-18 
(+ 3 days;or 
last IRX-2 
dose) 
Days 1-5 
Prior to 
Surgery 
Dayb 
25-30 
3, 6, 9, and 
12 months 
post-surgery 
Q 3 
mont
h 
Q 6 
month 
Q 6 
month 
 
KPS 
X 
X 
X 
X 
 
X 
X 
 
 
X 
CT (or MRI) of primary 
tumor and nodal areas  
X 
 
 
X 
 
 
 
 
 
X 
PET scan (optional)  
X 
 
 
X 
 
 
 
 
 
X 
CT scan of chest 
(annually post 
Randomization) 
Xa 
 
 
 
 
X 
X 
X 
X 
X 
Chemistry panel, 
PT/PTT, Hematology  
X 
Xj 
X 
X 
 
X 
 
 
 
X 
Pregnancy test, if 
applicable 
X 
 
 
 
 
Xk 
 
 
 
X 
Immunogenicity 
testingp 
X 
 
 
X 
 
X 
 
 
 
X 
Tumor Biopsy 
X 
 
 
 
 
 
 
 
 
Xe 
Tissue samples for 
Exploratory Analysis 
per Laboratory Manual 
X 
 
 
 
X 
 
 
 
 
 
Blood, serum and/or 
tissue samples per 
Laboratory Manual 
X 
 
 
X 
 
X 
 
 
 
X 
HPV Typingq 
 
 
 
 
X 
 
 
 
 
 
Concomitant medsl 
X 
X 
X 
X 
 
 
 
 
 
X 
Regimen Compliance 
 
 
X 
X 
 
X 
 
 
 
X 
Adverse eventsm 
 
X 
X 
X 
X 
X 
  
  
  
X 
SAEs n 
 
X 
X 
X 
X 
X 
 
 
 
X 
Survival statuso 
 
 
 
 
 
X 
X 
X 
X 
 


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Study Drug Administration Regimen 1 and 2 
Study Day 
Regimen 1 and Regimen 2 
Regimen 1 Only 
Booster Regimens† 
3, 6, 9, and 12 months post-surgery 
(-14 to +28 days) 
Booster Regimen 1 and  
Regimen 2 
Booster Regimen 1 Only 
-21 to -1 
Day 1 
Days 
2-21 
Any 10 
Days 
between 
Days 4-
21 
3 Days 
After 
Last IRX-
2 Dose 
Day 1 
Days 2-10 
Any 5 Days 
between 
Days 4 and 10 
Days 2-4 
After  Last 
Dose of IRX-2 
Cyclophosphamide  
 
X 
 
 
 
X 
 
 
 
Indomethacin f,g, 
omeprazole, zinc with 
multivitamins  
 
X 
X 
 
 
X 
X 
 
 
IRX-2 (Regimen 1 
only)i 
 
 
 
X 
 
 
 
X 
 
 
Injection Site Checks – Regimen 1 only 
Clinic or Visiting nurse 
 
 
 
Xh 
 
 
 
Xh 
 
Phone 
 
 
 
 
Xm 
 
 
 
Xm 


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Footnotes for Schedule of Events Table: 
a. Subjects will be screened for eligibility up to 21 days prior to randomization. CT of chest at screening acceptable if performed within 30 days of 
randomization. CT of chest need not be sent for central radiology review. PET, if performed, will satisfy this requirement. 
b. Surgery and subsequent assessments and interventions are to be performed on all subjects randomized (independent of arm). Surgery should be scheduled 
25-30 days after randomization and must take place no later than 35 days after randomization. In the event that Surgery is performed on Day 21 or 22, then 
evaluations required on Day-15 -18 and Days 1-5 Pre-op maybe combined.  
c. Booster regimens are to begin 3 months post-surgery and be given every 3 months for a total of 4 Booster treatments, i.e. at 3 , 6, 9, and 12 (-14 days to +28 
days)  months after surgical resection. † Any Booster injection which cannot be given during the specified timeframe should be omitted and the next 
scheduled booster regimen should be administered at the appropriated designated interval after surgical resection. Missed Booster injections must not be 
administered at a later date. The quarterly Booster Regimens must not be initiated until after completion and recovery from adjuvant radiation or 
chemoradiation as determined by the investigator. The investigator’s determination of adequate recovery should be based on review of any ongoing adverse 
events and the overall clinical status of the subject. Any uncertainty should be discussed with the Medical Monitor. 
d. All subjects must be assessed clinically with particular attention to primary tumor and regional nodes every 3 months during Years 1 & 2 and according to 
SOC at their local facility in Years 3 & 4. Protocol mandated follow-up will terminate 4 years after randomization. 
e. Suspicious lesions should be biopsied. If relapse confirmed, subjects should be restaged by CT, MRI and/or PET scans to restage disease and establish 
patterns of relapse. Possible second malignancies should be biopsied. In the event of disease recurrence, CT or MRI and/or PET scans of primary and 
recurrent disease, chest and any other clinically suspected disease sites should be done to document extent and pattern of recurrent, metastatic or second 
primary disease.  
f. 
Indomethacin and IRX-2 injections must be discontinued at least 48 hours prior to surgery. Administration of oral medications should be limited to 21 days, 
i.e. medication days should not be added to make up for missed days of medications. 
g. Missed days of oral medications should not taken later by the patient. i.e. medication days should not be added to make up for missed days of medications. 
h. Visiting Nurses may be used to administer IRX-2 in jurisdictions where approved. Any or all Booster injections† can be administered by Visiting Nurses in 
approved jurisdictions. 
i. 
The first and last days of IRX-2 for the Neoadjuvant Regimen must be administered at the study site. 
j. 
If CBC and chemistry panels are collected more than 7 days prior to Day 1, then these tests need to be repeated at Day 1. PT/PTT determinations are 
required at screening and pre-op only. Blood samples must be sent to the designated Central Laboratory. If more immediate results are required  for 
eligibility or during the study required, institutional laboratories may be used for treatment decisions, but duplicate specimens must be submitted to the 
Central Laboratory. 
k. Pregnancy tests can be done by Local laboratory prior to Booster Regimen† 
l. 
All concomitant medications should be documented at baseline. Thereafter, only medications given to treat a reported AE or SAE, or anti-tumor therapy 
(adjuvant as well as treatment for recurrence or a new primary) or considered immunosupressive or anti-proliferative should be documented. All updates to 
baseline medications should be documented. 
m. Adverse events will be collected from day of randomization until 30 days after the last dose of study regimen in the Treatment Period. Additionally AEs will 
be captured from the first day of each study regimen administration through 30 days after the last dose of the study regimen dosing in each of the Booster 
Regimens†. Any Adverse Event that the Investigator feels is related to study medication should be reported regardless of the timing of that event.  All AEs 


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will be monitored until stability or resolution (See Section 8.0). Follow-up phone calls to assess toxicity will be made to each subject on Day 21  (or 3 days 
after the last dose of IRX-2 for Regimen 1). If the date of the follow-up call occurs on a weekend or holiday the call should be made on the next available 
business day. 
n. All Serious adverse events (regardless of relatedness to study regimen) will be collected continuously from day of randomization until 30 days after the last 
dose of study regimen.  Any Serious Adverse Event that the Investigator feels is related to study medication should be reported regardless of the timing of 
that event.  All SAEs and will be monitored until resolution or stability. (See Section 8.0). 
o. Telephone calls for survival after progression to occur every 3 months if subject is not seen in follow-up. 
p. 5 mL of blood will be collected, >2 mL of serum will be sent to Central Laboratory and stored for immunogenicity testing against the active components of 
IRX-2. Samples will be collected at screening, after neoadjuvant therapy, prior to initiation of each of the Booster Regimens† and finally at 3 months after 
the last Booster Regimen†. 
q. HPV typing can be conducted at biospy, screening or on primary tumor removal. 
 


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5.2 
Study Procedures  
5.2.1 
Screening  
The purpose and procedures of the study will be fully explained to participants. Those wishing to 
enroll in the study will sign a written informed consent prior to initiating any protocol specific 
evaluations or procedures.  
The following screening evaluations are to be performed within 21 days (unless otherwise noted) 
prior to randomization: 
• Medical history, including assessment of all entry and exclusionary criteria, demographics 
(age, sex, race, menstrual status, weight, height), history of present illness, history of 
hypersensitivity (drug allergies), general medical history, and assessment of all current 
symptoms including severity. 
• Determination of Karnofsky performance status (Appendix 3). 
• History and current use of tobacco and/or alcohol. 
• Concomitant medication review. 
• Detailed head and neck exam, physical exam, including vital signs (blood pressure and pulse) 
and detailed description of the tumor and regional lymph node areas. 
• Endoscopic evaluation of tumor extent, including direct, indirect, or fiber-optic laryngoscopy. 
• Clinical laboratory assessments: 
o Hematology:  complete blood count (CBC), differential, platelet count, PT and PTT. 
o Serum chemistry: serum albumin, total protein, serum bilirubin, lactate dehydrogenase 
(LDH), ALT/SGPT, AST/SGOT, alkaline phosphatase, creatinine, blood urea nitrogen 
(BUN), glucose, and electrolytes. 
o Calculated creatinine clearance (Appendix 4) 
• Pregnancy test (serum or urine, females only) if appropriate. 
• CT or MRI imaging of primary site and neck and CT scan of chest with contrast for assessment 
of tumor (performed within 30 days of randomization). PET, if performed, may be substituted 
for CT scan of chest. 
• PET imaging (optional). 
• Tumor biopsy (within 3 months of randomization) for confirmation of diagnosis and research 
specimen. The standard of care when patients are evaluated for radical tumor resection is a full 
thickness tissue biopsy of the primary tumor. A rebiopsy of the primary tumor should be 
performed if the diagnosis has been by needle biopsy, but an adequate formalin fixed, paraffin 
embedded biopsy from a referring institution is sufficient.  
• Assessment of surgical resectability and tumor stage. 
• Collect blood samples for correlative studies.  
 


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All of the above evaluations, except for the collection of blood samples for correlative studies, are 
reasonable and medically necessary for the direct clinical management of the patient, and thus 
should be accepted for reimbursement under standard of care [Martin, 2014]. All surgical 
procedures and evaluations during and after surgery, other than administration of the Booster 
Regimens†, including all assessments for relapse or second tumors are also reasonable and 
medically necessary for the direct clinical management of the patient. 
5.2.2 
Randomization 
Subjects will be randomized to either Regimen 1 or Regimen 2. Randomization will be 2:1 in favor 
of Regimen 1. Treatments will be allocated to study subjects using minimization with a stochastic 
algorithm based on the range method will account for the major prognostic factors for HNSCC of 
the oral cavity (T and N stage) and study center to avoid imbalances in treatment allocation 
[Pocock, 1975. Full details of the treatment algorithm are specified in the Interactive Response 
Technologies (IRT) requirements document prepared by PPD (the CRO responsible for study 
subject randomization), but in order to avoid selection bias that might result from any 
foreknowledge, randomization algorithms for treatment assignment will not be disclosed to the 
Sponsor or Investigators. For all subjects, treatment with their assigned Regimen should begin 
within 7 days of randomization and surgery should be scheduled 25-30 days after randomization 
and must take place no later than 35 days after randomization.  
5.2.3 
Day 1  
The following procedures will be completed at this visit: 
• Interval history and assessment of all current symptoms (AEs) including severity. 
• Karnofsky performance status. 
• Record concomitant medications. 
• Brief general physical examination including weight and vital signs (blood pressure and pulse). 
• Head and neck examination. 
• Repeat laboratory assessments if more than 7 days since screening values obtained. 
o Hematology: CBC, differential, platelet count. 
o Serum chemistry: serum albumin, total protein, serum bilirubin, LDH, ALT/SGPT, 
AST/SGOT, alkaline phosphatase, creatinine, BUN, glucose, and electrolytes. 
• Administer the following medications: 
o Infusion of cyclophosphamide, 300 mg/m2. Steroids must not be administered as 
antiemetic agents since these might interfere with immunomodulation by IRX-2. 
Antiemetic regimen should include a serotonin (5-HT3) antagonist and lorazepam or 
equivalent medications. 
o Begin indomethacin (25 mg, TID) to be taken orally from Day 1 through Day 21. 
o Begin zinc with multivitamins, once daily, to be taken orally from Day 1 through Day 21. 
o Begin omeprazole, 20 mg, once daily, to be taken orally from Day 1 through Day 21. 


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5.2.4 
Days 4 to 21 (REGIMEN 1 Dosing ) 
 
IRX-2 should be administered by subcutaneous injection over any ten days between Days 4 and 
21. The last IRX-2 injection should be at least 48 hours prior to surgery.  
• IRX-2 should be administered by subcutaneous injection at two sites: 
o At or near the mastoid insertion of the sternocleidomastoid muscle (approximately 2 cm 
below the mastoid process) on the RIGHT side of the neck. 
o At or near the mastoid insertion of the sternocleidomastoid muscle (approximately 2 cm 
below the mastoid process) on the LEFT side of the neck. 
o In the event that tumor is present in one of the designated injection sites, the IRX-2 should 
not be injected into or immediately adjacent to tumor, but rather submandibularly 
approximately 2 cm posterior to the midline inferior aspect of the mandible.  
• Each subcutaneous injection will be approximately 1.0 mL of IRX-2 (corresponding to 115 
units of IRX-2 per injection or 2300 units during the total regimen). 
• On the first day of IRX-2 injections, subjects will be monitored for 15 minutes after the 
IRX-2 injections for signs or symptoms of any reaction. 
For subjects receiving Regimen 1, in the event of Grade 3 or higher toxicity, please see Section 
5.2.10. 
5.2.5 
Clinical Assessments on Days 15-18 
All subjects (Regimens 1 and 2) must return to the study site , on Days 15-18 (+3 days; or 
on the day of the last IRX-2 injection for subjects receiving Regimen 1) and the following 
evaluations must be performed (in the event that surgery is performed on Day 21 or 22, then 
evaluations required on Days-15 -18 and Days 1-5 Pre-op may be combined): 
• Interval history and assessment of all current symptoms including severity (AEs).  
• Head and neck examination. 
• Karnofsky performance status. 
• Clinical laboratory assessments: 
o Hematology: CBC, differential, platelet count. 
o Serum chemistry: serum albumin, total protein, serum bilirubin, LDH, ALT/SGPT, 
AST/SGOT, alkaline phosphatase, creatinine, BUN, glucose, and electrolytes. 
5.2.6 
One to Five Days Prior to Surgery 
The following procedures will be performed at this visit: 
• Interval history and assessment of all current symptoms including severity (AEs). 
• Record concomitant medications. 
• Karnofsky performance status. 


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• Brief physical exam including weight.  
• Head and neck exam and tumor assessment (documentation of change in tumor). 
• Indomethacin and IRX-2 injections must be stopped at least 48 hours before surgery. Subjects 
are scheduled to take indomethacin through Day 21. If surgery is to be performed on Day 21 
or 22, then the subject should discontinue IRX-2 and indomethacin on Day 19 or 20, 
respectively. 
• Repeat CT (or MRI) scan as at screening and, at participating centers, PET scan 
• Clinical laboratory assessments: 
o Hematology: CBC, differential, platelet count, PT and PTT.  
o Serum chemistry: serum albumin, total protein, serum bilirubin, LDH, ALT/SGPT, 
AST/SGOT, alkaline phosphatase, creatinine, BUN, glucose, and electrolytes. 
 
• Collect blood samples for correlative studies, including immunogenicity testing.  
• Data on compliance with protocol medications will be collected. 
5.2.7 
Surgery 
All subjects will undergo surgical resection of their tumor, reconstruction, and postoperative 
adjuvant therapy per usual standards of care according to the guidelines presented in Section 7.1. 
Surgery should take place 25-30 days after randomization and must take place no later than 35 
days after randomization. 
• All subjects will proceed to surgery, regardless of response to the IRX-2 regimen.  
• For all subjects, if the tumor progresses by Response Evaluation Criteria in Solid Tumors 
(RECIST v1.1) criteria (>20% in longest unilateral measurement), the investigator has the 
option of stopping investigational therapy and taking the subject immediately to surgery. 
• For all subjects, surgical and pathological data must be reported as described in this Protocol 
and the CRFs. 
• For all subjects, postoperative standard of care adjuvant radiation or chemoradiation therapy 
administered must be recorded. 
5.2.8 
IRX-2 Booster Regimen vs. Control Booster Regimen† 
Booster Regimens will not be given to subjects who had gross residual disease at surgery, recurrent 
or metastatic tumor or developed a second primary tumor.  
The quarterly Booster Regimens must not be initiated until after completion and recovery from 
adjuvant radiation or chemoradiation as determined by the investigator. The investigator’s 
determination of adequate recovery should be based on the review of any ongoing adverse events 
and the overall clinical status of the subject. Any uncertainty should be discussed with the Medical 
Monitor 
Patients who are receiving chronic anticoagulation in addition to aspirin, including  heparins, 
warfarin, oral anticoagulation or other platelet function inhibitors, may also initiate the Booster 


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Regimens. If more than Grade 1 injection-related ecchymoses are observed, however, the IRX-2 
injections should be discontinued or alternately the chronic anticoagulation and/or aspirin should 
be held until completion of the IRX-2 injections. 
The following procedures will be completed prior to the initiation of each Booster Regimen: 
• Interval history and assessment of all current symptoms including severity (AEs). 
• Record concomitant medications. 
• Karnofsky performance status. 
• Brief physical examination including weight. 
• Head and neck examination.  
• Laboratory assessments. 
o Hematology: CBC, differential, platelet count. 
o Serum chemistry: serum albumin, total protein, serum bilirubin, LDH, ALT/SGPT, 
AST/SGOT, alkaline phosphatase, creatinine, BUN, glucose, and electrolytes. 
o Pregnancy test (serum or urine, females only) if appropriate. 
o Local laboratories may be used for treatment decisions, but duplicate specimens must be 
submitted to the Central Laboratory. 
• Collect blood samples for correlative studies, including immunogenicity testing.  
• Administer the following medications: 
o Infusion of cyclophosphamide, 300 mg/m2. Steroids must not be administered as 
antiemetic agents since these might interfere with immunomodulation by IRX-2. 
Antiemetic regimen should include a serotonin (5-HT3) antagonist and lorazepam or 
equivalent medications 
o Begin indomethacin (25 mg, TID) to be taken orally from Day 1 through Day 10. 
o Begin zinc with multivitamins to be taken orally once daily from Day 1 through Day 10. 
o Begin omeprazole, 20 mg, to be taken orally once daily from Day 1 through Day 10. 
o After each Booster Regimen, data on compliance with protocol medications will be 
collected. 
REGIMEN 1 ONLY 
• IRX-2 should be administered by subcutaneous injection into bilateral deltoid regions. 
• Each subcutaneous injection will be approximately 1.0 mL of IRX-2 (corresponding to 115 
units of IRX-2 per injection or 1150 units during the total regimen). 
• On the first day of IRX-2 injections, subjects will be monitored for 15 minutes after the IRX-2 
injections for signs or symptoms of any reaction.  


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Subcutaneous IRX-2 injections are given in bilateral deltoid regions for 5 days, between Days 4 
and Day 10, administered every 3, 6, 9 and 12 months (-14 days to +28 days) after surgical 
resection. Any Booster injection which cannot be given during the specified timeframe should be 
omitted and  the next scheduled Booster Regimen should be administered subsequently at the 
designated interval after surgical resection. Missed Boosters must not be administered at a later 
date. 
5.2.9 
Follow-up Schedule  
5.2.9.1 Protocol-Required Follow-up Monitoring 
Subjects will be assessed clinically by physical examination of the oral cavity and regional nodes 
every 3 months for Years 1 and 2 (-14 days to +28 days). All follow-up visits from Year 3 through 
Year 4 (i.e., Y3M6, Y3M12, Y4M6, Y4M12) should be performed via telephone to collect survival 
information. However, CT scans of the chest should still be obtained at 1, 2, 3 and 4 years after 
randomization and in the event of disease recurrence. Protocol mandated follow-up will end 4 
years after randomization. 
The following procedures will be performed at the Years 1 and 2 post-surgery follow-up visits: 
• Interval history and assessment of all current symptoms including severity (AEs). 
• Record concomitant medications. 
• Karnofsky performance status. 
• Brief physical exam including weight. 
• Head and neck exam. 
• Pregnancy test (serum or urine, females only) if appropriate every 3 months for Year 1 only. 
• Clinical laboratory assessments (every 3 months for Year 1 post-surgery; not done in Year 2):  
o Hematology: CBC, differential, platelet count. 
o Serum chemistry: serum albumin, total protein, serum bilirubin, LDH, ALT/SGPT, 
AST/SGOT, alkaline phosphatase, creatinine, BUN, glucose, and electrolytes. 
o Serum for immunogenicity testing. 
Assessment should focus on physical exam, symptoms or signs relevant to the primary tumor site, 
regional disease (including lymph nodes), metastatic spread, second malignancy, and treatment 
complications. 
CT scans of the chest should be performed yearly x 4 and as clinically indicated or in the event of 
a second primary tumor. Suspected disease recurrence must also be confirmed by needle aspiration 
or other biopsy procedure and should be documented by physical exam (if possible) and additional 
radiology studies to confirm the extent of disease. 
5.2.9.2 Survival 
Telephone calls for survival after progression to occur every 3 months if subject is not seen in 
follow-up. 


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5.2.9.3 Additional Follow-up Testing  
Each investigator may obtain additional radiologic or other tests as recommended by applicable 
guidelines or according to his/her usual standard of practice, so long as consistency is maintained 
in obtaining them for all subjects, regardless of study arm. The Medical Monitor as well as the 
Data Safety Monitoring Board will assess adherence to this requirement at each study site.  
5.2.10 
Regimen 1 and 2 Dose Modification 
For subjects receiving Regimen 1, in the event of Grade 3 or higher toxicity, no further IRX-2 
should be injected and indomethacin should be discontinued for that course. Subsequent booster 
courses† can be attempted but should be permanently discontinued if the same Grade 3 toxicity 
reoccurs. In the event of Grade 2 toxicity, treatment should be delayed until stable and then 
resumed per protocol. Treatment should be discontinued in a subject if the treatment is delayed for 
more than 7 days, except that treatment with IRX-2 and zinc may be continued per protocol in a 
subject intolerant of indomethacin. 
For subjects receiving Regimen 2, in the event of Grade 3 or higher toxicity, indomethacin should 
be discontinued for that course. Subsequent booster courses† can be attempted but should be 
permanently discontinued if the same Grade 3 toxicity reoccurs. In the event of Grade 2 toxicity, 
treatment should be delayed until stable and then resumed per protocol. Treatment should be 
discontinued in a subject if the treatment is delayed for more than 7 days, except that treatment 
zinc-containing multivitamins may be continued per protocol in a subject intolerant of 
indomethacin. 
 
 


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6 
STUDY ASSESSMENTS  
6.1 
Endpoint Assessments 
6.1.1 
Primary Endpoint - EFS 
EFS will be assessed by physical examination at routine follow-up visits every 3 months after 
surgery for the first 2 years and every 6 months during years 3 and 4 and by chest CT scans 
performed yearly x 4 years. During years 3-4 subjects will be contacted by phone to determine survival 
status, and will be assessed in person (eg, physical exam, laboratory evaluations, etc.) according to standard 
of care at their enrolling institution. Any indication of recurrence occurring at these SOC visits should be 
followed up with a confirmatory imaging and reported in the Recurrence CRF folder.  Progression prior 
to surgical resection will not be considered an Event, but failure to resect tumor that was apparent 
at randomization for any reason or the presence of gross residual disease at surgery will be 
considered an Event. (The rationale for this definition of EFS is that increased cellular infiltration 
into tumor induced by the IRX-2 Regimen might result in increase in tumor size but not represent 
tumor progression. A secondary exploratory analysis, however, will be performed in which EFS 
will be assessed starting from randomization by RECIST).  
Progression after resection should be confirmed by biopsy, but in the absence of biopsy 
confirmation, unequivocal clinical evidence of progression in the primary or nodal sites or distant 
metastatic disease using RECIST v1.1 criteria will be accepted as progression. Scans (CT, MRI or 
PET) should be performed to restage disease and establish patterns of relapse. The date of 
progression will be the date on which the decision not to resect tumor that was apparent at 
randomization is made or the date upon which the Investigator first observes recurrent locoregional 
or metastatic disease by physical or radiologic examination.  
Death for any cause will also be considered an Event.  
Diagnosis of a second malignancy will not be considered an Event, but date of diagnosis, site and 
histology will be collected.  
6.1.2 
Secondary Endpoints 
6.1.2.1 Overall Survival 
Survival data will be collected in all subjects (phone contact after progression will be sufficient). 
When the subject comes to clinic and/or is contacted by phone, the date of that contact is to be 
reported as an update of the subject’s survival. 
6.1.2.2 Safety and Feasibility 
Safety of each Regimen and feasibility of the Booster Regimens† will be assessed by the incidence 
and severity of AEs, SAEs, and subject discontinuations. All subjects will be assessed for AEs as 
detailed on the Study Schedules (Section 5.1) and in Section 5.2 and evaluated for AEs  as noted 
in Section 8.0. 
6.1.3 
Exploratory Endpoints 
Exploratory endpoints will be determined in subjects enrolled at selected clinical sites. The 
Sponsor may at any time alter or discontinue some or all of these endpoints so long as additional 
clinic visits, radiology studies or blood draws are not initiated.  


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Analyses of some or all of the Exploratory Endpoints will be conducted by the Sponsor or 
designated representatives at intervals depending on the availability of sufficient data.  
6.1.3.1 Key Exploratory Endpoints 
6.1.3.1.1 
Tumor Size 
Change in tumor size will be determined by a comparison of the imaging studies (CT or MRI) 
obtained pre-treatment and just prior to surgery. Percent changes in tumor size will be determined 
by central radiology review by radiologists blinded to the treatment Regimen. 
6.1.3.1.2 
Functional Imaging 
At selected institutions, change in functional imaging will be determined by a comparison of the 
FDP-PET scans obtained pre-treatment and just prior to surgery. Percent changes in glycolytic 
activity will be estimated by central radiology review by radiologists blinded to the treatment 
Regimen. 
6.1.3.1.3 
Lymphocyte Infiltrates 
Lymphocyte infiltrates in the pre-treatment tumor biopsies and the surgical specimens will be 
determined and compared. Subsets of lymphocytes will be evaluated including total T cells and 
naïve, cytotoxic and regulatory T cells. The analyses may include quantifications of cellular 
infiltrates and degree of activation by immunohistochemistry including (but not limited to): CD3, 
CD8, CD68 (myeloid derived suppressor cells), CD45RO and Fox P3 on lymphocytes and MHC 
class I and II and PDL1 on tumor cells. Other immune subsets and activation markers may be 
evaluated. Tumor gene expression signatures may also be performed. Lymphocyte infiltrates and 
changes after treatment will also be evaluated using T cell receptor (TCR) repertoire analyses 
performed on extracted RNA. These studies will be performed by one or more external contract 
research organizations without knowledge of the treatment regimen received.  
6.1.3.2 Additional Exploratory Endpoints 
6.1.3.2.1 
Pathology 
Each surgical specimen must undergo complete pathological assessment of the resected specimen 
with particular attention to size and extent of tumor (pathological T stage), tumor differentiation 
(well, moderately, or poorly), number and location of involved lymph nodes (pathological 
N stage), extracapsular extension of tumor, closeness of tumor to resection margins (described in 
mm), perineural involvement, and vascular invasion (blood or lymphatic). 
6.1.3.2.2 
Prognostic Factors 
Prognostic and predictive factors and clinical-pathologic-immunologic correlates, including, for 
example, nutritional status (body mass index, albumin), absolute lymphocyte count, lymphocyte 
subsets and histological differences in the surgical specimen and gene expression profiles will be 
evaluated for correlation with disease-free survival, recurrence, second primary tumors, and 
patterns of disease recurrence. 
6.1.3.2.3 
HPV Status 
Although the impact of HPV status is greater in patients with oropharyngeal cancer than in patients 
with non-oropharyngeal HNSCC, it still impacts outcomes in the latter group of patients [Chung, 


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2014]. Therefore, HPV status will be assessed by p16 expression and its relationship to clinical 
outcome and benefit from the IRX-2 Regimen will be explored.  
6.1.3.2.4 
T cell Receptor Profile 
The peripheral T cell receptor profile prior to and post treatment during the first year of the trial 
will be used to explore relationships to clinical outcome. 
6.1.3.2.5 
RNA Expression 
RNA expression profiling of immune-inflammatory markers will be examined. 
 


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7 
DISCIPLINE STANDARDS OF CARE 
7.1 
Surgery 
Surgery and subsequent assessments and interventions are to be performed on all subjects 
randomized (independent of arm). For subjects randomized to either Arm, surgery is to be 
scheduled 25-30 days after randomization and must take place no later than 35 days after 
randomization.  
Within one to five days before surgery, all subjects are to be re-evaluated by interval history, 
performance status, brief physical examination, and CBC with differential and serum chemistry 
tests to assess clinically significant changes between study entry and surgery. 
For all subjects, the surgical procedure and reconstruction should be designed to resect all gross 
tumor achieving tumor-free surgical margins. The surgery should be planned and performed to 
resect the tumor and the surgical plan is to be defined and described prior to surgery. 
For all subjects, if tumor progression by RECIST v1.1 criteria (>20% in longest unilateral 
measurement) is documented by radiographic study, the Investigator may, but is not required to, 
discontinue immunotherapy and take the subject immediately to surgery. 
7.2 
Radiation Therapy 
Postoperative radiation therapy is to be given per protocol and NCCN guidelines 
(http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf) regardless of treatment 
arm unless medically contraindicated, as soon as adequate recovery from surgery has occurred but 
no later than 8 weeks after surgery. Protocol guidelines, consistent with NCCN Guidelines, are 
that subjects should receive radiation (unless medically contraindicated) if there is evidence of any 
of the following: 
1. 
Extracapsular nodal spread 
2. 
Multiple positive nodes (N2 or N3 disease) 
3. 
Nodal disease in levels IV or V 
4. 
Positive margins (ink at margin or margin of 5 mm or less) 
5. 
pT3 or pT4 primary 
6. 
Perineural invasion 
7. 
Vascular invasion (blood or lymph vessel) 
Standard dose and fractionation of radiation therapy are recommended, i.e., 60–66 Gy in 30–33 
fractions of 2 Gy each over 6 to 7 weeks. Use of alternative radiation approaches, e.g. intensity 
modulated radiation therapy, concomitant or subsequent radiation boost, or hyperfractionated 
radiation, is permissible. Detailed information regarding standard of care adjuvant radiation 
therapy will be collected.  
Aggressive nutritional support, including a feeding tube, is strongly recommended in all subjects 
who are to receive postoperative radiation therapy.  


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7.3 
Chemotherapy with Radiation  
Postoperative chemotherapy should be given concurrent with radiation therapy to subjects who 
meet the protocol and NCCN specified guidelines, regardless of treatment arm. Concurrent 
chemotherapy should be given (unless medically contraindicated) to subjects with:  
1. 
Microscopic positive margin (surgical margin of 5 mm or less), or 
2. 
Extracapsular nodal extension. 
Chemoradiation should also be considered for subjects with other adverse risk factors as indicated 
in Section 7.2 and the NCCN Guidelines Version 2.2014. It is important that these criteria be 
followed independent of the treatment arm to which the subject was randomized. Detailed 
information regarding standard of care adjuvant chemoradiation therapy will be collected. 
The preferred regimen for subjects who receive postoperative chemotherapy is cisplatin every 3 
weeks at 100 mg/m2 for three doses [Bernier, 2004; Cooper, 2004; Bernier, 2006]. If a subject is 
not medically able to receive cisplatin on the preferred dose and schedule, cisplatin may be 
administered at 50 mg or 40 mg/m2 intravenously weekly during radiation therapy [Bachaud, 
1996]. Alternatively, if a subject is unable to receive cisplatin because of inadequate renal function, 
hearing impairment or neuropathy, carboplatin, AUC = 2, given weekly for the duration of 
radiation therapy, or AUC = 5, given every 3 weeks x three doses, may be substituted. The reason 
a subject is not able to receive cisplatin must be documented. If a subject is unable to continue 
adjuvant cis- or carboplatin, the subject should not receive alternative chemotherapy but should 
complete the planned course of radiation therapy. Administration of chemotherapy and supportive 
care for chemoradiation therapy should be given according to institutional standard practice, but 
must include adequate hydration and antiemetics. 
Suggested guidelines for cisplatin dose modification are as follows: 
On the day that treatment is due, absolute neutrophil count (ANC) must be ≥1000 and platelets 
>100,000/mm3 for administration of cisplatin. If these parameters are not met, hold 
chemotherapy and reinstitute as indicated below: 
1. 
Neutropenia: If ANC <1000, withhold treatment until >1000, and then give 100% of 
dose. 
2. 
Thrombocytopenia: If platelets are <100,000/mm3, withhold dose until ≥100,000/mm3, 
and then give 100% dose. 
3. 
Neurological motor or sensory neuropathy that impairs function – discontinue cisplatin, 
there will be no substitution of other platinum drugs. 
4. 
Renal: 
Creatinine 
 
 
Creatinine Clearance  
Dose 
≤1.2 mg/dL       or  
>50 mL/min  
 
100 mg/m2 
>1.2 mg/dL      and  
40-50 mL/min  
 
60 mg/m2 
>1.2 mg/dL      and  
<40 mL/min  
 
Discontinue 
 


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8 
ADVERSE EVENTS, REPORTING REQUIREMENTS, AND STOPPING RULES 
8.1 
Adverse Event Definitions 
Definitions of AEs will follow the International Conference on Harmonization E6: Good Clinical 
Practice Step 5, Consolidated Guideline 1.5.96, April 1998 edition, and are summarized below. 
For this study, the investigational product is the IRX-2 regimen, including IRX-2, 
cyclophosphamide, indomethacin, and zinc-containing multivitamins. 
An adverse drug experience (event) is any new undesirable medical occurrence or change 
(worsening) of an existing condition in a subject that occurs from the day of randomization until 
30 days after the last dose of study regimen, whether or not considered to be drug related. 
Therefore, AEs are treatment-emergent signs and symptoms. This includes those events occurring 
from drug overdose, whether accidental or intentional, from drug abuse or from drug withdrawal. 
In general, abnormal laboratory findings without clinical significance based on the investigator’s 
judgment are part of the database and should not be recorded as AEs. 
Adverse events reported by the subject or observed by the investigator will be individually listed 
on an AE CRF page. The signs and symptoms, date of onset, duration, action taken, severity, 
outcome to date, and relationship to the study drug will be recorded. The severity of AEs will be 
graded according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE), Version 4.03 toxicity criteria. Severity will be classified as described in 
Section 8.1.4. 
Adverse events will be collected from day of randomization until 30 days after the last dose of 
study regimen in the Treatment Period. Additionally, AEs will be captured from the first day of 
each study regimen administration through 30 days after the last dose of the study regimen dosing 
in each of the Booster Regimens†. Any Adverse Event that the Investigator feels that is related to 
study medication should be reported regardless of the timing of that event.  All AEs will be 
monitored until stability or resolution. Follow-up phone calls to assess toxicity will be made to 
each subject on Day 21 (or 3 days after the last dose of IRX-2 for Regimen 1).  If the date of the 
follow-up call occurs on a weekend or holiday, the call should be made on the next available 
business day. 
All Serious Adverse Events regardless of relatedness to study regimen, will be collected 
continuously from day of randomization until 30 days after the last dose of study regimen. Any 
Serious Adverse Event that the Investigator feels is related to study medication should be reported 
regardless of the timing of that event. All SAEs will be monitored until resolution or stability.  
Adverse events of Grade 3-4 will be reviewed by the Medical Monitor, who may assess with the 
Site Principal Investigator whether to modify or discontinue study treatment. 
At each visit, the investigator will be prompted to report AEs and SAEs as “not”, “possibly,” or 
“definitely” related to the assigned study regimen. 
Any pregnancy occurring during the clinical study should be reported immediately using the 
pregnancy report form. 


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8.1.1 
Definition of Serious and Life Threatening Adverse Events 
A serious adverse drug experience (event) is any AE occurring at any dose that results in any of 
the following outcomes: 
• Death 
• Is life-threatening  
- A life-threatening adverse drug experience is any AE that places the subject, in the view of 
the investigator, at immediate risk of death from the reaction as it occurred. This does not 
include a reaction that, had it occurred in a more severe form, might have caused death. 
• A persistent or significant disability/incapacity 
• Inpatient hospitalization or prolongation of existing hospitalization, except that planned 
hospitalization during days in clinic and surgery or hospitalization for the social reasons or the 
convenience of the subject or physician shall not be considered an SAE  
• A congenital anomaly/birth defect 
• Important medical event 
- Important medical events that may not result in death, be life-threatening, or require 
hospitalization but may jeopardize the subject and require medical or surgical intervention 
to prevent one of the outcomes listed above   
8.1.2 
Protocol Defined Adverse Events for SAE Reporting 
- 
For purposes of this protocol, the following are considered important medical events 
and thus are to be reported as SAEs (even if they are not life-threatening or do not 
require hospitalization): fistula formation, wound dehiscence or other clinically 
significant complications of surgical or other treatment of advanced oral cavity 
cancer and any immune related adverse events.  
8.1.3 
Definition of Relationship to Study Regimen and Drug 
Association or relatedness to the study regimen will be graded as either “not”, “possibly,” or 
“definitely” related to the study regimen. Determination of relatedness is to the entire study 
Regimen as a whole, i.e. not to the individual components of the Regimen, and is defined as 
follows: 
• Definitely, characterized as an AE that 
- Follows direct temporal sequence from regimen administration. 
- Abates upon discontinuation of the regimen. 
- Cannot be explained by the known characteristics of the subject’s clinical state or by other 
modes of therapy administered to the subject.  
• Possibly, characterized as an AE that 
- Follows a reasonable temporal sequence from regimen administration. 
- Abates upon discontinuation of the regimen. 
- Could have been produced by the subject’s clinical state or by other modes of therapy 
administered to the subject. 


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• Not Related, characterized as an AE that 
- Does not follow any temporal sequence from regimen administration.  
- Is explained by the subject’s clinical state or by other modes of therapy administered to the 
subject. 
Association or relatedness of observed AEs to the study drug, IRX-2, will be determined by 
comparison of AEs between Regimens 1 and 2 as described below in Section 9.6 and in the SAP. 
8.1.4 
Definition of Severity 
The severity of adverse changes in physical signs or symptoms will be graded according to the 
NCI-CTCAE v4.03. For AEs not listed in the table, the severity of adverse changes in physical 
signs or symptoms will be classified as follows: 
 
Grade 1: 
Mild (transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required) 
Grade 2: 
Moderate (mild to moderate limitation in activity, some assistance may be needed; 
no or minimal medical intervention/therapy required) 
Grade 3: 
Severe (marked limitation in activity, some assistance usually required;  
medical intervention/therapy required, hospitalizations possible) 
Grade 4: 
Life-threatening (extreme limitation in activity, significant assistance  
required; significant medical intervention/therapy required, hospitalization or 
hospice care probable) 
Grade 5: 
Death 
8.1.5 
Definition of Action Taken 
None: 
No action taken with regard to the study regimen  
Interrupted: 
The study regimen was stopped but restarted after the subject’s symptom 
abated. The subject was rechallenged with the study regimen. 
Discontinued: The study regimen was permanently stopped 
8.1.6 
Definition of Outcome to Date 
Resolved with sequelae: 
The subject has recovered from the AE with observable residual 
effects 
Resolved without sequelae: 
The subject has fully recovered from the AE with no observable 
residual effects 
Unresolved: 
The AE is present and observable 
Death: 
The subject died as a result of the AE 


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Lost to Follow-up: 
Source documentation confirms that repeated attempts to  
contact subject have failed 
8.2 
Notification of Serious or Unexpected Adverse Events 
In case of any SAE, regardless of the relationship to study treatment or expectedness, the 
investigator must complete the SAE information in the CRF which will be submitted to the PPD 
Safety Surveillance Unit. In the event that the CRF is not available to the investigator, he/she 
should complete the SAE Form and  fax a copy to the appropriate number below. 
All SAE phone and fax lines are toll-free and in operation 24 hours a day, 7 days a week. 
SAE Reporting (US and Canada):  1-888-483-7729 (phone):   1-888-529-3580 (fax) 
SAE Reporting (Europe):  +44 1223 374 240 (phone):           +44 1223 374 102 (fax) 
SAE Reporting (Mexico, Central and South America):  +55 11 4504 4801 (phone)  
 
 
 
 
 
 
 
 
+55 11 3958 0983 (fax) 
Within 24 hours from the time that the investigator is aware of an SAE, copies of the medication 
logs and any other required documentation will be faxed to PPD using the appropriate numbers.  
Contact information will be provided to the site along with other study information. The Safety 
Surveillance Unit will report the SAE to the Sponsor’s Medical Monitor within 1 working day of 
the event. 
For SAE reports, the Sponsor is required by US regulation (21 Code of Federal Regulations [CFR] 
Part 312.32) to: 
• Notify the FDA by telephone or fax of any unexpected fatal or life-threatening event associated 
with use of the drug as soon as possible but in no event later than 7 calendar days after initial 
receipt of the information. A written safety report will be submitted to the FDA no later than 
15 calendar days after initial notification of the information. Determination of expectedness to 
the IRX-2 Regimen should be made with consideration of the Reference Safety Information in 
the most current version of the IRX-2 Investigator’s Brochure or more current published 
reference safety information; 
• Notify all participating investigators of any SAE that is serious, assessed as definitely or 
possibly related to the study medication, and unexpected; and notify the FDA and investigators 
of any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. Each notification 
shall be made in writing as soon as possible but in no event later than 15 calendar days after 
receiving the initial information; 
• Monitor the nature, frequency, and severity of SAEs known to be associated with the drug to 
identify an unexpected change in the nature, or increase in the rate of occurrence or severity of 
these events. If a change in the nature or an increased frequency or severity is identified, FDA 
must be notified in writing within 15 calendar days of the determination; and 
• Submit to FDA any follow-up information in a safety report as soon as possible, but in no event 
later than 15 calendar days, as well as information amendments and annual progress reports. If 


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an AE initially not determined to be reportable, is reportable, the information shall be 
submitted in a safety report as soon as possible, but in no event later than 15 calendar days 
after determining that the event is reportable. 
All safety issues should be communicated with the Sponsor who will forward them to the FDA or 
give instructions for PPD or the designated CRO to do so.  
In the EU, applicable SAEs will be reported to the national Ministry of Health (or National 
Competent Authority) as required by 2001/20/EC: http://ec.europa.eu/health/human-use/clinical-
trials/directive/index_en.htm#ct6. When the new clinical trial regulation EU No536/2014 becomes 
applicable, safety reporting will follow these and any future applicable requirements. 
It is the responsibility of the Sponsor and the designated CRO to ensure that Ethics Committee, 
competent authorities and participating investigators are informed of applicable SAEs in 
accordance with local requirements. 
8.3 
Pregnancies  
Subjects should be instructed to immediately inform the Investigator if they or a partner become 
pregnant during the study or within 1 year after the last study treatment. A Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor. Study treatment must be 
discontinued and monitoring of the patient should continue until conclusion of the pregnancy. Any 
abortion or congenital anomaly/birth defect in a child born to a female patient or partner exposed 
to study treatment should be classified as a Serious Adverse Event.  
8.4 
Reporting of Deaths  
Any death occurring in the study population that is not preceded by the diagnosis of recurrent or 
progressive cancer must be reported within 24 hours using the SAE report form. The Safety 
Surveillance Unit will immediately report the death to the Sponsor and to the Medical Monitor. 
8.5 
Stopping Rules for Excessive Toxicity Leading to Delay  in Definitive Surgery  
In the current trial, 35 days has been set as the limit of the acceptable interval from the date of 
randomization to the date of surgery. Taking into consideration time from diagnostic biopsy to 
referral to a study center or Investigator, time to obtain Informed Consent, time for screening 
procedures prior to randomization and time from randomization to beginning of the assigned study 
Regimen, this limit is consistent with the data obtained in the prior Phase 2 study and with current 
clinical experience is an academic medical center (see Section 1.3.2.5). 
Subjects in whom surgical resection takes place >35 days after randomization will be reviewed in 
order to establish whether toxicity from either neoadjuvant Regimen 1 or Regimen 2 is associated 
with unacceptable delays in definitive surgery. If either the Investigator or the DSMB Chair 
designates that the delay in surgical resection is definitely or possibly related to Study Regimen 
(per Section 8.1.2), the delay will be considered “definitely or possibly related to Study Regimen.”  
This review will initially be undertaken by the Chair of the DSMB after every cohort of 20 patients 
has had surgery (hence after 20, 40, 60, etc. patients). 
1. Overall toxicity: the incidence of overall delay (both Regimens combined) will be estimated 
and will be considered too high if the lower limit of “surgery later than 35 days considered 
definitely or possibly related to Study Regimen” of the 95% confidence interval excludes 15%. 


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This would be the case based on the normal approximation, for instance, if 8 out of 20 patients 
had delayed surgery, or 12 out of 40, etc. as shown in the following table: 
 
# of subjects evaluated 
# needed with surgery after 
day 35 to trigger “Stopping 
Rule” 
20 
8 
40 
12 
60 
16 
80 
20 
100 
24 
 
2. Toxicity to experimental treatment: the difference in delay between Regimen 1 and Regimen 
2 will be estimated, and Regimen 1 will be considered to have excessive delay if the lower 
limit of the the 95% confidence interval for the difference excludes 15%. This would be the 
case, for instance, if 5 out of 10 patients had delayed surgery in Regimen 1 vs. none out of 10 
in Regimen 2, or 8 out of 20 vs. none out of 20, etc. 
 
Note that no adjustment has been made for multiplicity (which is appropriate for a toxicity 
assessment) and that two-sided confidence intervals have been used in determination of the above 
numbers. 
If either of these stopping rules were met and confirmed by a meeting of the entire DSMB, the 
Sponsor would be notified and the study would be placed on clinical hold until the Sponsor and 
relevant regulatory authorities agree that the study should proceed.  


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9 
STATISTICAL CONSIDERATIONS 
9.1 
Sample Size Considerations 
Randomization will be 2:1 in favor of Regimen 1. Treatments will be allocated to study subjects 
using minimization with a stochastic algorithm based on the range method. Minimization will 
account for the major prognostic factors for HNSCC of the oral cavity (T and N stage) and study 
center to avoid imbalances in treatment allocation [Pocock, 1975]. 
The proposed clinical study is a randomized, Phase 2b clinical trial with a relaxed p-value 
[Rubinstein, 2005; Ratain, 2007; Buyse, 2006]. A total of approximately 100 subjects will be 
randomized. The study will have a power of 61% to detect an increase in EFS of 15% in subjects 
who receive Regimen 1 compared to those who receive Regimen 2, using a one-sided p-value of 
0.10. The results of this trial, in conjunction with supportive data that may be obtained from 
analyses of co-primary exploratory and additional exploratory studies, will be adequate for use by 
the Company to make a decision on required size, optimal endpoints and chance of success of a 
potential randomized, double-blind Phase 3 clinical trial. 
Assuming that the EFS at 24 months will be 50% for subjects receiving Regimen 2, this trial will 
have 61% power (one-sided  = 0.1) to detect an increase in EFS of 15% (i.e. to 65%) at 24 months 
(hazard ratio [HR] = 0.62) for the subjects receiving Regimen 1. The required number of EFS 
events for the assessment of the primary endpoint is 51. The primary analysis will be of the entire 
population as randomized (intent-to-treat).  
Assuming that the OS at 36 months will be 55% for subjects receiving Regimen 2, this trial will 
have 66% power (one-sided  = 0.1) to detect an increase in OS of 15% (i.e. to 70%) at 36 months 
(HR = 0.60) for the subjects receiving Regimen 1. The required number of deaths for the 
assessment of the OS endpoint is 51.  
9.2 
Subject Populations 
Intention-To-Treat (ITT) Population: The ITT population consists of all randomized subjects, 
whether or not they receive the Regimen to which they were randomized as intended. This is the 
primary population for the primary and secondary efficacy analyses. 
Per-protocol Population: The PP population consists of subjects who did not have a major protocol 
deviation, received one dose of cyclophosphamide as neo-adjuvant therapy, and received  at least 
80% of the intended IRX-2 biologic as neo-adjuvant therapy in Regimen 1. For Regimen 2, the PP 
population consists of subjects who did not have a major protocol deviation and received one dose 
of cyclophosphamide as neo-adjuvant therapy. This population will be used with a descriptive 
intent to assess the effect of therapy when given in optimal conditions. 
Safety Population: The Safety population includes all subjects who received at least one dose of a 
study Regimen. Subjects will be analyzed according to the treatment that they actually received. 
This is the primary population for the safety analysis. 
9.3 
Methods to be Used for Handling Missing or Spurious Data 
No imputation of missing data will be applied. Spurious data will be ignored. 


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9.4 
Efficacy 
Efficacy analyses will be carried out on all randomized subjects (ITT population).  
The primary evaluation will be based on event-free survival (EFS), which is defined as the time 
from randomization to progression after surgery, or at surgery, if failure to resect gross disease, or 
at time of death from any cause after randomization. Progression will be defined by RECIST v 
1.1. 
The Kaplan-Meier estimates of the proportion of subjects event-free at 3 months, 6 months, 12 
months, 24 months, 36 months and 48 months as well as median EFS, 25th percentile and 75th 
percentile along with their 95% log-log transformed confidence intervals will be computed. 
The primary analysis will be based on the inferential comparison between the 2 treatments by 
using a stratified log-rank test at the 0.1 significance level (one-sided). The test will be stratified 
on major prognostic factors for HNSCC of the oral cavity (T and N stage). A randomization test 
will be used, and will be complemented by the usual asymptotic log-rank test to assess the 
sensitivity of the analysis to the method used to allocate treatments to patients. 
A stratified Cox proportional-hazards model, with the same stratification variables as used in the 
stratified log-rank test, will be applied to estimate the hazard ratio (HR) and corresponding two-
sided 95% confidence interval.  
A sensitivity exploratory analysis of event-free survival accounting for disease progression 
occurring prior to surgery will be conducted. The same methods applied for the primary analysis 
of EFS will be used. 
A second sensitivity exploratory analysis of event-free survival defined as the time from surgery 
to first recurrence or death from any cause will be conducted. Subjects who do not undergo surgery 
or in whom surgery does not result in resection of all disease will have their DFS assigned as an 
event at time 0. Subjects who undergo surgery and who do not have an event will be censored at 
the last event assessment date. The same methods applied for the primary analysis of EFS will be 
used. 
The secondary evaluation will be based on overall survival (OS), which is defined as the time from 
randomization to death for any cause. The same methods applied for the primary analysis of EFS 
will be used. 
Further details on statistical analyses to be performed on the aggregate collected data for the 
primary and secondary endpoints will be described in the Statistical Analysis Plan (SAP). 
Analyses of exploratory endpoints will be conducted. Analyses of some or all the exploratory 
endpoints will be conducted by the Sponsor or designated representatives throughout the study. 
These results from these exploratory analyses will be handled in a manner so as not to affect the 
analysis of the primary and secondary endpoints. 
9.5 
Interim Analysis 
An interim analysis is foreseen for EFS in approximately Q1 2019. This analysis will use a 
conservative O’Brien-Fleming-like Lan-DeMets spending function to assess efficacy. 
The spending function provides full flexibility as to when this interim analysis will be conducted, 
with the exact significance level to be used being determined by the number of events available at 


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the interim analysis time. Assuming the interim analysis is carried out at 70% information fraction, 
the significance level to be used for the interim analysis will be equal to 0.05, and the significance 
level to be used for the final analysis will be equal to 0.0857.  
It is estimated that approximately 36 EFS events (about 70% of the required number) will have 
occurred by Q1 2019, and that the 51 EFS events required for the final analysis of EFS will have 
occurred by Q1 2020. There will be no assessment for futility as part of the Interim Analysis.  
It is estimated that approximately 34 deaths (about 66% of the required number) will have occurred 
by Q1 2020, and that the approximately 51 deaths required for the final analysis of OS will have 
occurred by Q1 2022. 
9.6 
Safety 
Safety analyses will be carried out from the date of randomization on all randomized subjects who 
receive any treatment (Safety population). Exposure to protocol defined study regimen will be 
summarized and adverse events will be summarized by system organ class and preferred term 
coded in accordance with MedDRA version 17.1. Regimen 1 will be compared to Regimen 2 in 
terms of: 
• each type of AE at worst grade of severity 
• any AE at worst grade of severity 
• SAEs 
• withdrawals (and reasons for them) 
• dose modifications (and reasons for them) 
• treatment interruptions (and reasons for them)  
• abnormal laboratory findings that are considered clinically significant by the investigator 
• early deaths, defined as deaths due to any cause occurring within 75 days after the date of 
randomization 
Grade at baseline and worst grade during study will be summarized for laboratory parameters that 
can be graded with NCI CTCAE version 4.03. Abnormality grade (normal, abnormal) at baseline 
and worst abnormality grade during study will be summarized for all other laboratory parameters. 
Change from baseline values for weight, pulse rate, systolic and diastolic blood pressure as well 
as Karnofsky Performance Score will be summarized at scheduled visits. Physical and head and 
neck abnormal examination at baseline and worst abnormality during study will be summarized. 


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10 
ETHICAL AND REGULATORY CONSIDERATIONS 
10.1 
Protection of Human Subjects 
This study has been designed and will be conducted in accordance with the principles outlined in 
the Declaration of Helsinki. 
10.2 
Informed Consent 
Once a patient is referred for consideration in the study, that individual’s history and current status 
will be completely evaluated, and treatment recommendations will then be discussed thoroughly 
with the patient. The investigator will discuss with the patient any other treatments that may be 
available and their relative value compared to the possible use of IRX-2 therapy. The risks and 
hazards of the procedures will be explained to the patient. The investigator shall seek consent only 
under circumstances that provide the individual sufficient opportunity to consider whether or not 
to participate and that minimize the possibility of coercion or undue influence. The information 
that is given to the individual shall be in understandable language. No informed consent may 
include any exculpatory language through which the individual is made to waive or appear to 
waive any of their legal rights, or releases or appears to release the investigator, IRX Therapeutics, 
the institution, or its agents from liability for negligence. The patient, or legal guardian, must be 
able to comprehend the informed consent form and sign prior to enrollment. The subject will then 
receive a signed copy of the consent form. 
10.3 
Institutional Review Board or Independent Ethics Committee 
The investigator must obtain approval for the study from the institutional review board (IRB) or 
independent ethics committee (IEC). Prior to initiation of the study, the Sponsor or its designee 
must receive a copy of the written communication from the IRB/IEC indicating approval of the 
protocol and consent form. All changes to the protocol must be reviewed and approved prior to 
implementation, except where purely administrative or necessary to eliminate apparent immediate 
hazards to subjects. The investigator is responsible for obtaining annual IRB/IEC renewal through 
the duration of the study. Copies of the investigator’s report and the IRB/IEC’s continuance of 
approval must be submitted as directed. The Sponsor or its designee must be notified within 5 
working days of any withdrawal of approval by the reviewing IRB/IEC. 


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11 
STUDY ADMINISTRATION 
11.1 
Monitoring Plan 
11.1.1 
Pre-study Site Evaluation 
The Sponsor or designated personnel will visit each study center to confirm the site’s qualifications 
for implementing this protocol. The protocol and study procedures will be reviewed with the 
investigator and study personnel. This visit may be combined with the study initiation visit. 
11.1.2 
Site Initiation 
The Sponsor or designated personnel will visit the site to train personnel on all protocol elements, 
study procedures, and safety, and to confirm site readiness prior to enrollment. There should be 
visits to clinical (surgery, radiation therapy, medical oncology), diagnostic radiology, and 
pathology study participants. 
11.1.3 
Interim Monitoring 
Interim monitoring visits will be scheduled at regular intervals throughout the study, with the 
timing being dependent on subject enrollment. Generally, the study monitor will compare the data 
entered on the CRFs with the hospital or clinic records (primary source documents) and check for 
protocol compliance, including verification of informed consent, all subject visit dates, all AEs, 
all concomitant medications, and all key efficacy observations. In addition, the investigator site 
file containing essential documents, study drug accountability, and supporting records will be 
reviewed. Findings from this review will be summarized in writing and presented to the 
investigator, and the dates of the visits will be recorded by the study monitor in a sign-in log to be 
kept at the study site. During monitoring visits, the study coordinator and investigator should be 
available, all subject records and regulatory documents must be available, and a suitable 
environment must be provided for review of study-related documents. 
11.1.4 
Study Close-out 
At the study’s conclusion, there will be a monitoring close-out visit at which time a final review 
and reconciliation of all study and regulatory documents and study drug will be performed. 
11.1.5 
Site Responsibility 
The procedures defined in the protocol and in the CRFs will be carefully reviewed by the 
investigator and his/her staff, prior to the time of study initiation, to ensure appropriate 
interpretation and implementation. No deviations from the protocol should be made. Minor 
exceptions may be approved on a case-by-case basis and must be authorized by the Medical 
Monitor or his designee and documented in writing, and the Sponsor informed. Significant 
deviations that may impact patient safety or study integrity will be reported to the institutional 
Ethics Committee and may result in termination of study participation. Any changes to the protocol 
will originate from the Sponsor in the form of an amendment. 


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11.2 
Compliance Statement 
This study will be conducted in accordance with the US CFR, Title 21, Parts 11, 50, 54, 56 and 
312; the Good Clinical Practices: Consolidated Guideline (E6), International Conference on 
Harmonization, the Food and Drug Administration Guidance for Industry: Computerized Systems 
Used in Clinical Trials, the ethical principles that have their origins in the Declaration of Helsinki 
and all applicable country-specific and local regulations. All required study information will be 
archived as required by regulatory authorities. 
11.3 
Investigational Product Accountability 
The principal investigator is responsible for investigational product accountability. The 
investigator or his/her designee must maintain a current record of the receipt and disposition of 
investigational product, including dates, quantity, kit, lot, and subject numbers. The investigator 
or responsible designee will record the receipt, dispensation by subject number, kit number, lot 
number, and disposition of the product onto the drug accountability forms provided by sponsor or 
its designee. A copy of these will be collected and returned to sponsor or its designee on an ongoing 
basis. The investigator will maintain a copy for the institutional records. Drug dispensing records 
must also be maintained. 
In addition, a quality assurance release form and a shipping form (if applicable) will be included 
with each shipment stating lot number and quantity of product shipped. The investigator or 
responsible designee will sign the forms in the designated area, which certifies the receipt of 
supplies, and retain a copy for the institutional records. At sites that are dispensing drug, the 
investigator, or designee, will also maintain a dispensing record of IRX-2. 
Used and unused drug vials will be destroyed by the responsible pharmacist at each clinical site 
after study monitor reconciliation procedures. Specific instructions will be provided in the 
Investigational Product Guidelines. Each site will be requested to use the procedures that are 
locally approved for destruction of biological products, and the details of such destruction will be 
captured on a form provided in the guidelines. These forms will be retained and available for 
inspection at the study site. 
11.4 
Study Documents and Access to Records 
It is the responsibility of the investigator and study staff to maintain a comprehensive and 
centralized filing system of all study-related documentation, which is suitable and accessible for 
inspection/review at any time by the study monitor, the Sponsor or its designee, IRB/ IEC, and 
regulatory authorities. Elements should include, but are not limited to: 
• Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under Part 54 of Title 21 of the CFR. In addition, 
the investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 1 year 
following the completion of the study.  
• Study Files, containing the curriculum vitae of all investigators and his/her designees, FDA 
Form 1572, Financial Disclosure Forms, the protocol with all amendments, the IB, copies of 
all pre-study documentation, local lab certifications and lab normal ranges, and all 
correspondence to and from local Regulatory Authorities to the Sponsor or its designee. 


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• Subject Files, containing the completed original supporting source documentation and the 
signed informed consent form(s). 
• Completed Electronic Case Report Forms 
• Dispensing records of test agents. 
The sponsor shall ensure that the important documents of the clinical trial, including the protocol, 
are kept for at least ten years after the end or termination of the trial.  
11.5 
Study Closure/Study Termination 
The study will end when all treated subjects have either been followed for 4 years after the date 
of randomization, have expired or have withdrawn consent for survival follow-up. 
The Sponsor reserves the right to close the investigational site or terminate the study at any time 
for any reason, including but not limited to the following: 
• Successful completion of the study 
• Failure of the investigator to comply with the protocol or Good Clinical Practice/ International 
Conference on Harmonization guidelines 
• Safety concerns 
• Inadequate recruitment of subjects at a clinical site 
• Decision to close the study for any reason 
Disclosure of study termination will be made immediately to the IRB/IEC by the investigator. 
11.6 
Quality Assurance 
The Sponsor and all designees will ensure the integrity of all data collected and calculations made 
during the conduct of the study according to their quality assurance standards of operations. Edit 
checks will be run on the data and queries issued. All data will undergo 100% review. 
11.7 
Confidentiality and Publication Policy 
This trial will be listed in clinical trial databases as appropriate, e.g., www.clintrials.gov. 
No written or oral reports or information about the trial, its progress, or results obtained for the 
duration of the trial will be provided by any investigator or anyone associated with this study, to 
anyone not involved in the trial other than to the Sponsor or its designees, or in confidence to the 
IRB/IEC, without the express, written permission of the Sponsor. 
Following the completion of the study, the data will be reported at a scientific meeting and by 
publication in a scientific journal at the discretion of the participating investigators, voting in 
proportion to the number of subjects each has entered on the study. Since this research effort is a 
multi-center investigation, each investigator acknowledges that participation in the protocol 
involves a commitment to present and/or publish the data from this study in a cooperative manner 
prior to doing so on an individual basis. 
Any abstract or publication presenting results of this trial shall be given to the Sponsor for review 
and approval at least 30 days prior to intended submission to a scientific journal for publication or 


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to a scientific meeting for oral or poster presentation. The Sponsor will not arbitrarily withhold or 
delay agreement to present the results of this study in appropriate scientific settings. 
The Sponsor endorses published guidelines for the publication and presentation of clinical study 
results. The Sponsor and the investigators acknowledge their intent to resolve in good faith any 
differences of opinion regarding presentation or publication of study results. 


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12 
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†Important Note: 
 
As of Protocol Amendment 4 all adjuvant, booster administration of study regimen has been 
discontinued. Randomized subjects will receive neoadjuvant treatment and will then be 
discontinued from further study drug. After discontinuation from study drug, all subjects will be 
followed for progression and survival as described in the protocol. 


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Appendix 1: 
American Joint Committee on Cancer: Staging of Head and Neck 
Cancer-Lip and Oral Cavity – TNM Staging 
AJCC Staging Manual, 7th Edition 
 
Definitions of TNM 
Primary Tumor (T) 
Oral 
Cavity 
T1 
Tumor 2 cm or less in greatest dimension 
 
 
T2 
Tumor >2 cm but not more than 4 cm in greatest 
dimension 
 
 
T3 
Tumor >4 cm in greatest dimension 
 
 
T4a 
Tumor invades adjacent structures (eg, through cortical 
bone, into deep [extrinsic] muscle of tongue 
[genioglossus, hyoglossus, palatoglossus, styloglossus], 
maxillary sinus, skin of face 
 
 
T4b 
Tumor invades masticator space, pterygoid plates, or 
skull base and/or encases internal carotid artery 
Regional lymph nodes (N) 
N0 
No regional lymph node metastasis 
 
 
N1 
Metastasis in a single ipsilateral lymph node ≤ 3 cm in 
greatest dimension 
 
 
N2a 
Metastasis in a single ipsilateral lymph node >3 cm but 
≤ 6 cm in greatest dimension 
 
 
N2b 
Metastasis in multiple ipsilateral lymph nodes, none >6 
cm in greatest dimension 
 
 
N2c 
Metastasis in bilateral or contralateral lymph nodes, 
none >6 cm in greatest dimension 
 
 
N3 
Metastasis in a lymph node >6 cm in greatest dimension 
Distant Metastasis 
 
MX 
Distant metastasis cannot be assessed 
 
 
M0 
No distant metastasis 
 
 
M1  
Distant metastasis 
From AJCC Staging Manual, 7th Edition 
 
 


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Appendix 2: 
American Joint Committee on Cancer: Staging of Head and Neck 
Cancer-Lip and Oral Cavity – Stage Grouping AJCC Staging Manual, 
7th Edition 
 
Stage Grouping 
Stage 0 * 
Tis 
N0 
M0 
Stage I * 
T1 
N0 
M0 
Stage II  
T2 
N0 
M0 
Stage III 
T3 
N0 
M0 
T1 
N1 
M0 
T2 
N1 
M0 
T3 
N1 
M0 
Stage IVA 
T4a 
N0 
M0 
T4a 
N1 
M0 
T1 
N2 
M0 
T2 
N2 
M0 
T3 
N2 
M0 
T4a 
N2 
M0 
Stage IVB* 
Any T 
N3 
M0 
T4b 
Any N 
M0 
Stage IVC* 
Any T 
Any N 
M1 
* Stages 0, I, IVB and IVC are not eligible for the study. 
From AJCC Staging Manual, 7th Edition 


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Appendix 3: 
Karnofsky Performance Status 
Score 
Performance 
100 
Normal:  no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self; unable to carry on normal activity or do active work. 
60 
Requires occasional assistance from others; but able to care for most needs. 
50 
Requires considerable assistance from others, frequent medical care. 
40 
Disabled:  requires special care and assistance. 
30 
Severely disabled:  hospitalization indicated, death not imminent. 
20 
Very sick, hospitalization necessary, active supportive treatment necessary. 
10 
Moribund:  fatal processes are progressing rapidly. 
0 
Dead 
Source: Karnofsky D, Abelman W, Craver L, Burchenal J. The use of nitrogen mustards in the 
palliative treatment of carcinoma. Cancer 1948;1:634-56. 
 


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Appendix 4: 
Calculation of Creatinine Clearance by Cockcroft-Gault Equation 
 
Formula:   Creatinine Clearance  = Sex (Male = 1.0, Female = 0.85) * ((140 - Age) /  
 
 
(Serum Creatinine)) * (Weight / 72) 
 
 
Online calculator may be found at  
 
http://reference.medscape.com/calculator/creatinine-clearance-cockcroft-gault