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

Primary Purpose

Cervical Squamous Cell Carcinoma In Situ, Vulvar High Grade Squamous Intraepithelial Lesion

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cyclophosphamide
Indomethacin
IRX-2
Laboratory Biomarker Analysis
Multivitamin
Omeprazole
Placebo
Therapeutic Conventional Surgery
Sponsored by
University of Southern California
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cervical Squamous Cell Carcinoma In Situ

Eligibility Criteria

25 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • USC / Norris Comprehensive Cancer Center
  • University of Oklahoma Health Sciences Center, Stephenson Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Arm I (IRX-2)

Arm II (placebo)

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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.

Full Information

First Posted
August 28, 2017
Last Updated
September 3, 2023
Sponsor
University of Southern California
Collaborators
National Cancer Institute (NCI), Brooklyn ImmunoTherapeutics, LLC
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1. Study Identification

Unique Protocol Identification Number
NCT03267680
Brief Title
IRX-2 Regimen in Treating Women With Cervical Squamous Intraepithelial Neoplasia 3 or Squamous Vulvar Intraepithelial Neoplasia 3
Official Title
A Two-Cohort Randomized 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)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
November 8, 2017 (Actual)
Primary Completion Date
November 8, 2024 (Anticipated)
Study Completion Date
November 8, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Southern California
Collaborators
National Cancer Institute (NCI), Brooklyn ImmunoTherapeutics, LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cervical Squamous Cell Carcinoma In Situ, Vulvar High Grade Squamous Intraepithelial Lesion

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
11 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I (IRX-2)
Arm Type
Experimental
Arm Description
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.
Arm Title
Arm II (placebo)
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Indomethacin
Intervention Description
Given PO
Intervention Type
Biological
Intervention Name(s)
IRX-2
Intervention Description
Given via submucosal injection or SC
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Dietary Supplement
Intervention Name(s)
Multivitamin
Other Intervention Name(s)
Geritol, Vitamin Supplements (NOS)
Intervention Description
Given zinc-containing multivitamin PO
Intervention Type
Drug
Intervention Name(s)
Omeprazole
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Placebo
Other Intervention Name(s)
placebo therapy, sham therapy
Intervention Description
Given via submucosal injections or SC
Intervention Type
Procedure
Intervention Name(s)
Therapeutic Conventional Surgery
Intervention Description
Undergo surgical resection
Primary Outcome Measure Information:
Title
Pathologic response
Description
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).
Time Frame
Week 25
Secondary Outcome Measure Information:
Title
Incidence of adverse events of IRX-2 administration
Description
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.
Time Frame
Up to week 25

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lynda Roman, MD
Organizational Affiliation
University of Southern California
Official's Role
Principal Investigator
Facility Information:
Facility Name
USC / Norris Comprehensive Cancer Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
University of Oklahoma Health Sciences Center, Stephenson Cancer Center
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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