IRX-2 Regimen in Treating Women With Cervical Squamous Intraepithelial Neoplasia 3 or Squamous Vulvar Intraepithelial Neoplasia 3

A Two-Cohort, Open-label Phase 2 Trial of the IRX-2 Regimen in Women With Squamous Cervical Intraepithelial Neoplasia 3 (CIN 3) or Vulvar Intraepithelial Neoplasia 3 (VIN 3)

This randomized phase II trial studies how well an IRX-2 Regimen works in treating women with cervical squamous intraepithelial neoplasia 3 or squamous vulvar intraepithelial neoplasia 3. The IRX-2 Regimen consists of a single dose of cyclophosphamide, followed by 21 days of indomethacin, zinc-containing multivitamins, and omeprazole. IRX-2, a human cell-derived biologic with multiple active cytokine components, may act as an immune booster to stimulate the immune system. Giving cyclophosphamide and IRX-2 may work better at treating cervical squamous intraepithelial neoplasia or squamous vulvar intraepithelial neoplasia.

Study Overview

• Status: Terminated
• Conditions: Cervical Squamous Cell Carcinoma In Situ; Vulvar High Grade Squamous Intraepithelial Lesion
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Cyclophosphamide; Procedure: Therapeutic Conventional Surgery; Drug: Indomethacin; Drug: Omeprazole; Biological: IRX-2; Dietary supplement: Multivitamin; Other: Placebo

Detailed Description

PRIMARY OBJECTIVES:

I. To compare the proportion of subjects who achieve a pathologic complete response (CR) or partial response (PR) in regimen 1 versus regimen 2 at week 25, based on the resected surgical specimen.

SECONDARY OBJECTIVES:

I. To evaluate the toxicity and feasibility of administration of IRX-2 in subjects with confirmed cervical intraepithelial neoplasia (CIN) 3 or vulvar intraepithelial neoplasia (VIN) 3.

II. To evaluate multiple parameters to assess the activity of the IRX-2 regimen for the treatment of CIN 3 or VIN 3: the occurrence of clinical CRs or PRs at weeks 6, 13 and 25.

III. To evaluate multiple parameters to assess the activity of the IRX-2 regimen for the treatment of CIN 3 or VIN 3: frequency of elimination of human papillomavirus (HPV) in cervical or vulvar tissue using a commercial HPV genotyping assay and viral load determination by quantitative polymerase chain reaction (PCR).

IV. To evaluate multiple parameters to assess the activity of the IRX-2 regimen for the treatment of CIN 3 or VIN 3: analysis of the immune infiltrates in the resected surgical specimens.

V. To evaluate multiple parameters to assess the activity of the IRX-2 regimen for the treatment of CIN 3 or VIN 3: immunophenotypic analysis of peripheral blood lymphocytes.

VI. To evaluate multiple parameters to assess the activity of the IRX-2 regimen for the treatment of CIN 3 or VIN 3: frequency of serum antibodies to HPV E6, E7 and L1 proteins by enzyme-linked immunosorbent assay (ELISA).

VII. To evaluate multiple parameters to assess the activity of the IRX-2 regimen for the treatment of CIN 3 or VIN 3: ribonucleic acid (RNA) expression profiling of immune-inflammatory markers from post-treatment resected surgical specimens.

OUTLINE: Patients are randomized to 1 of 2 arms.

Arm I: Patients receive cyclophosphamide intravenously (IV) on day 1 and IRX-2 via submucosal injections in the cervix or subcutaneously (SC) for vulvar lesions on days 4-7. Patients also receive indomethacin orally (PO) three times daily (TID), zinc-containing multivitamins (PO) once daily (QD) and omeprazole orally (PO) on days 1-21.

Arm II: Patients receive cyclophosphamide IV on day 1 and placebo via submucosal injections in the cervix or SC for vulvar lesions on days 4-7. Patients also receive indomethacin PO TID, zinc-containing multivitamins PO QD and omeprazole PO on days 1-21.

In both arms, treatment repeats every 6 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Beginning week 25, patients undergo surgical resection.

After completion of study treatment, patients are followed up at 1-8 weeks after surgery.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC / Norris Comprehensive Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center, Stephenson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed squamous CIN 3, or VIN 3 (usual type only)
• The subject is either surgically sterile, postmenopausal, or agrees to practice an effective method of birth control as determined by the investigator (to be continued throughout the study period), except that subjects with CIN 3 are not permitted to use a cervical cap or diaphragm for contraception
• White blood cell > 2,500/ mcL (> 2.5 x 10^9/L)
• Absolute neutrophil count > 1,000/ microliter (> 1 x 10^9/L)
• Platelet count > 75,000/ mcL (> 75 x 10^9/L)
• Hemoglobin >= 8 g/dL (>= 80 g/L) (subjects who have received a transfusion or erythropoietin up to one week prior to receiving the first dose of cyclophosphamide are eligible for the study)
• International normalized ration (INR) or prothrombin time (PT) < 1.5 x ULN (upper limit of normal)
• Activated partial thromboplastin time (aPTT) < 1.5 x ULN
• Serum creatinine < 1.5 x ULN
• Total bilirubin < 2.0 x ULN unless thought to be related to inherited bilirubin conjugation disorder (ie Gilbert?s disease)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN
• The subject is geographically accessible for ongoing follow-up and is committed to comply with the designated visits
• The subject is capable of understanding and complying with the protocol and has signed the enrollment informed consent form at screening

Exclusion Criteria:

• For subjects with cervical dysplasia: evidence of atypical glandular cells or adenocarcinoma in situ (ACIS) based on cervical cytology, colposcopy or biopsy
• For subjects with either cervical or vulvar squamous dysplasia: evidence of microinvasive squamous carcinoma based on cytology, colposcopy or biopsy
• Pregnancy or lactation
• Allergy to ciprofloxacin or other quinolones (because ciprofloxacin is used in preparation of IRX-2)
• Allergy to indomethacin (a necessary component of the regimen) or to acetylsalicylic acid (aspirin) due to likely allergy cross-reaction
• Aldara (imiquimod) for the topical treatment of lower genital tract warts or dysplasia within 3 months of study enrollment
• Known to be positive for human immunodeficiency virus-1 (HIV-1) antibody, human immunodeficiency virus-2 (HIV-2) antibody, hepatitis B surface antigen, or hepatitis C virus antibody
• Known to have other immunodeficiency diseases, including cellular immunodeficiencies, hypogammaglobulinemia, or dysgammaglobulinemia
• Immunotherapy (eg, interferons, tumor necrosis factor, interleukins) or biological response modifiers (granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, macrophage colony-stimulating factor) or any investigational drug within 3 months of study enrollment
• Concurrent treatment with systemic corticosteroids at a dose of >= 5 mg/day of prednisone (or equivalent)
• Subjects should not take aspirin (except for low-dose aspirin as prescribed for vascular disease) or other non-prescribed, non-steroidal anti-inflammatory agents from randomization to surgery
• An infectious process or any other significant illness such as an autoimmune disease or advanced age that in the opinion of the investigator would compromise the subject?s ability to mount an immune response

• Impaired hepatic, renal or hematological function, evidenced by:

  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin >= 2 times upper limit of normal (ULN),
  • Serum creatinine >= 2 times ULN, or
• Clinically significant active cardiovascular disease, including a history of myocardial infarction within the past 6 months, heart failure as defined by New York Heart Association classes III or IV, and/or blood pressure greater than 160/90 mm Hg (1 repeat measure allowed no more than 5 minutes after the first measurement)
• History of severe allergic reaction to insect bites or stings, or to any biologic pharmaceutical product, including compounds similar to the test article
• Any medical contraindications, allergies or previous therapy that would preclude treatment with the components of the IRX-2 regimen, i.e., cyclophosphamide, indomethacin, zinc-containing multivitamins or omeprazole
• Donation or loss of > 450 mL of blood or plasma within 30 days of randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (IRX-2); Patients receive cyclophosphamide IV on day 1 and IRX-2 via submucosal injections in the cervix or SC for vulvar lesions on days 4-7. Patients also receive indomethacin PO TID, zinc-containing multivitamins PO QD and omeprazole PO on days 1-21. Treatment repeats every 6 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Beginning week 25, patients undergo surgical resection.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Cyclophosphamide; Given IV; Procedure: Therapeutic Conventional Surgery; Undergo surgical resection; Drug: Indomethacin; Given PO; Drug: Omeprazole; Given PO; Biological: IRX-2; Given via submucosal injection or SC; Dietary supplement: Multivitamin; Given zinc-containing multivitamin PO; Other Names: Geritol; Vitamin Supplements (NOS)
Active Comparator: Arm II (placebo); Patients receive cyclophosphamide IV on day 1 and placebo via submucosal injections in the cervix or SC for vulvar lesions on days 4-7. Patients also receive indomethacin PO TID, zinc-containing multivitamins PO QD and omeprazole PO on days 1-21. Treatment repeats every 6 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Beginning week 25, patients undergo surgical resection.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Cyclophosphamide; Given IV; Procedure: Therapeutic Conventional Surgery; Undergo surgical resection; Drug: Indomethacin; Given PO; Drug: Omeprazole; Given PO; Dietary supplement: Multivitamin; Given zinc-containing multivitamin PO; Other Names: Geritol; Vitamin Supplements (NOS); Other: Placebo; Given via submucosal injections or SC; Other Names: placebo therapy; sham therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic Response	Complete Response (CR) is defined as absence of intraepithelial neoplasia, Partial Response (PR) is defined as a lower grade of dysplasia than present at baseline (for example, grade 3 decreasing to grade 1).	Week 25

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events of IRX-2 Administration	Will be assessed by the incidence and severity of adverse events, serious adverse events, as classified and graded according to the current version of the Common Terminology Criteria for Adverse Events version 4.	Up to 30 months

Collaborators and Investigators

• Sponsor: University of Southern California
• Collaborators: National Cancer Institute (NCI); Brooklyn ImmunoTherapeutics, LLC
• Investigators: Principal Investigator: Lynda Roman, MD, University of Southern California

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2017
• Primary Completion (Actual): August 4, 2023
• Study Completion (Actual): March 13, 2024

Study Registration Dates

• First Submitted: August 28, 2017
• First Submitted That Met QC Criteria: August 28, 2017
• First Posted (Actual): August 30, 2017

Study Record Updates

• Last Update Posted (Actual): April 13, 2025
• Last Update Submitted That Met QC Criteria: March 26, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Carcinoma; Neoplasms; Carcinoma in Situ; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Enzyme Inhibitors; Gout Suppressants; Antirheumatic Agents; Reproductive Control Agents; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Tocolytic Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Cyclophosphamide; Omeprazole; Indomethacin
• Other Study ID Numbers: 5GYN-16-2 (Other Identifier: USC / Norris Comprehensive Cancer Center); P30CA014089 (U.S. NIH Grant/Contract); NCI-2017-01402 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No