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.

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.

Inclusion Criteria:

1. Pathologically confirmed (histology or cytology) 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 30 days after last dose of study regimen. Males with a partner of childbearing potential must use condoms with spermicide from the date of screening to 30 days after their last dose of study regimen
11. Negative urine/serum pregnancy test, if applicable

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

   • 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
   • 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:

   • involvement of pterygopalatine fossa, maxillary sinus, or facial skin;.
   • gross extension of tumor to the skull base;
   • pterygoid plate erosion;
   • sphenoid bone or foramen ovale involvement;
   • direct extension to involve prevertebral fascia;
   • extension to superior nasopharynx or Eustachian tube;
   • direct extension into the neck with involvement of the deep neck musculature (neck node fixation);
   • 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;
   • direct extension of neck disease to involve the external skin;
   • direct extension to mediastinal structures;
   • 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

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 bacterial 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.

Sponsor shall have the right to first publication. Following first publication, the Institution and/or Principal Investigator may publish data or results from the Study; provided, however, that the Institution and/or Principal Investigator submits the proposed publication to Sponsor for review at least 60 days prior to the date of the proposed publication. Sixty days shall be extended to 120 days if Sponsor determines that the publication contains patentable matter.