Clinical trial NCT02609386: IRX-2 Regimen in Patients With Newly Diagnosed Stage II, III, or IVA Squamous Cell Carcinoma of the Oral Cavity
Official 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Squamous Cell Carcinoma of the Oral Cavity
Keywords: Head and Neck Neoplasms
Immunotherapy
Cancer
Oral Cavity
Lead sponsor: Brooklyn ImmunoTherapeutics, LLC
Sponsor class: INDUSTRY
First posted: 2015-11-20
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Event-free Survival (EFS)- Number of Participants With an Event
timeFrame: From randomization up until the data cut-off date of June 2, 2022 (approximately 76 months)
measure: EFS- Time to Event
timeFrame: From randomization up until the data cut-off date of June 2, 2022 (approximately 76 months)
Secondary outcomes:
measure: Overall Survival (OS)- Number of Participants With an Event
timeFrame: From randomization up until the data cut-off date of June 2, 2022 (approximately 76 months)
measure: OS- Time to Event
timeFrame: From randomization up until the data cut-off date of June 2, 2022 (approximately 76 months)
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Banner University Medical Center
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas For Medical Sciences
state: Arkansas
city: Los Angeles
country: United States
facility: USC Norris Comprehensive Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Atlanta
country: United States
facility: Emory University - Winship Cancer Center
state: Georgia
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: New Hyde Park
country: United States
facility: Monter Cancer Center - North Shore LIJ
state: New York
city: New York
country: United States
facility: Lenox Hill Hospital
state: New York
city: Oklahoma City
country: United States
facility: University of Oklahoma
state: Oklahoma
city: Portland
country: United States
facility: Providence Cancer Center
state: Oregon
city: Philadelphia
country: United States
facility: Hospital of The University of Pennsylvania
state: Pennsylvania
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner
city: Goiânia
country: Brazil
facility: Instituto Goiano de Oncologia e Hematologia (INGOH)
city: Londrina
country: Brazil
facility: Instituto do Câncer de Londrina
city: Rio de Janeiro
country: Brazil
facility: Instituto Nacional do Cancer (INCA)
city: São José do Rio Prêto
country: Brazil
facility: Hospital de Base de São José do Rio Preto
city: São Paulo
country: Brazil
facility: Instituto Brasileiro de Controle do Câncer
city: São Paulo
country: Brazil
facility: Instituto do Cancer do Estado de São Paulo - ICESP
city: Toronto
country: Canada
facility: Sunnybrook Research Institute
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital Glasgow
Study officials:
affiliation: University of Michigan Hospitals
name: Gregory T Wolf, MD, FACS
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.