IRX-2 Regimen in Patients With Newly Diagnosed Stage II, III, or IVA Squamous Cell Carcinoma of the Oral Cavity

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.

• IRX-2 (Biological), also known as Immunotherapy: Method of Administration: Administered for 10 days as subcutaneous bilateral injections in the upper neck.
• Cyclophosphamide (Drug), also known as Cytophosphane, Cytoxan: Method of Administration: Cyclophosphamide is administered once by IV
• Indomethacin (Drug), also known as NSAID, Indocin: Method of Administration: Indomethacin is administered orally for 21 days.
• Zinc-containing multivitamin (Dietary supplement), also known as Zinc, Multi-vitamin: Method of Administration: Zinc-containing multivitamin is administered orally for 21 days.
• Omeprazole (Drug), also known as Proton pump inhibitor, Prilosec: Method of Administration: Omeprazole is administered orally for 21 days

Primary outcomes

• Event-free Survival (EFS)- Number of Participants With an Event [From randomization up until the data cut-off date of June 2, 2022 (approximately 76 months)]: EFS is defined as the time from randomization until progression after surgery, or at surgery, if failure to resect gross disease, or at time of death from any cause after randomization.
• EFS- Time to Event [From randomization up until the data cut-off date of June 2, 2022 (approximately 76 months)]: EFS is defined as the time from randomization until progression after surgery, or at surgery, if failure to resect gross disease, or at time of death from any cause after randomization. Assessment of progression/disease recurrence occurred by physical exam and annual imaging for the duration of the follow up portion of the study. Median EFS was estimated using the Kaplan-Meier method.

Secondary outcomes

• Overall Survival (OS)- Number of Participants With an Event [From randomization up until the data cut-off date of June 2, 2022 (approximately 76 months)]: OS was defined as the time from randomization to death due to any cause.
• OS- Time to Event [From randomization up until the data cut-off date of June 2, 2022 (approximately 76 months)]: OS was defined as the time from randomization to death due to any cause. Data for partipants who were alive at the end of the study were censored at the last known alive date. Median OS was estimated using the Kaplan-Meier method.

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Event-free Survival (EFS)- Number of Participants With an Event (Primary), Count of participants, Participants: Regimen 1 31; Regimen 2 15
• EFS- Time to Event (Primary), Median, Months: Regimen 1 48.3 (11.4 to NA); Regimen 2 NA (18.8 to NA) (p 0.6176)
• Overall Survival (OS)- Number of Participants With an Event (Secondary), Count of participants, Participants: Regimen 1 19; Regimen 2 11 (p 0.3889)
• OS- Time to Event (Secondary), Median, Months: Regimen 1 NA (NA to NA); Regimen 2 NA (42.6 to NA) (p 0.5091)

Adverse events

Time frame: AEs/SAEs were collected over a period of approximately 60 days (i.e., from the day of randomization through 30 days after the last dose of study drug). If booster treatments were administered, AEs/SAEs were collected through 30 days after the last dose of study drug. AE data were collected over a period of approximately 2 years and 10 months. All cause mortality was assessed through study completion, approximately 76 months.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: One of the initial secondary objectives of the study was to compare the feasibility of each booster regimen (Regimen 1 vs Regimen 2) post-surgery. However, as a significant number of patients were unable to receive booster treatments due to tolerability issues and/or their post-surgery/post-adjuvant chemoradiation therapy status, booster regimens were discontinued and analysis of booster feasibility was not performed due to insufficient data for a meaningful, statistically sound analysis.

• Wolf GT, Fee WE Jr, Dolan RW, Moyer JS, Kaplan MJ, Spring PM, Suen J, Kenady DE, Newman JG, Carroll WR, Gillespie MB, Freeman SM, Baltzer L, Kirkley TD, Brandwein HJ, Hadden JW. Novel neoadjuvant immunotherapy regimen safety and survival in head and neck squamous cell cancer. Head Neck. 2011 Dec;33(12):1666-74. doi: 10.1002/hed.21660. Epub 2011 Jan 31. PMID 21284052
• Berinstein NL, Wolf GT, Naylor PH, Baltzer L, Egan JE, Brandwein HJ, Whiteside TL, Goldstein LC, El-Naggar A, Badoual C, Fridman WH, White JM, Hadden JW. Increased lymphocyte infiltration in patients with head and neck cancer treated with the IRX-2 immunotherapy regimen. Cancer Immunol Immunother. 2012 Jun;61(6):771-82. doi: 10.1007/s00262-011-1134-z. Epub 2011 Nov 6. PMID 22057678
• Results publication: Wolf GT, Liu S, Bellile E, Sartor M, Rozek L, Thomas D, Nguyen A, Zarins K, McHugh JB; INSPIRE Trial Clinical Investigators. Tumor infiltrating lymphocytes after neoadjuvant IRX-2 immunotherapy in oral squamous cell carcinoma: Interim findings from the INSPIRE trial. Oral Oncol. 2020 Dec;111:104928. doi: 10.1016/j.oraloncology.2020.104928. Epub 2020 Jul 29. PMID 32738599

• Study Protocol and Statistical Analysis Plan (PDF, 2018-10-15)

• Gregory T Wolf, MD, FACS, Principal investigator, University of Michigan Hospitals