Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Carcinoma, Squamous Cell

Carcinoma in Situ

Squamous Intraepithelial Lesions of the Cervix

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Cervical Intraepithelial Neoplasia

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Inflammatory Agents

Analgesics

Reproductive Control Agents

Gastrointestinal Agents

Micronutrients

Cyclophosphamide

Indomethacin

Omeprazole

Vitamins

Zinc

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antacids

Anti-Ulcer Agents

Proton Pump Inhibitors

Enzyme Inhibitors

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Tocolytic Agents

Cyclooxygenase Inhibitors

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.

IRX-2

Laboratory Biomarker Analysis

Multivitamin

Placebo

Therapeutic Conventional Surgery

Lynda Roman, MD

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.

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.

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

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)

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).

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.

National Cancer Institute (NCI)

Brooklyn ImmunoTherapeutics, LLC

University of Southern California

Uterine Cervical Dysplasia

Precancerous Conditions

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Neoplasms, Squamous Cell

Central Nervous System Depressants

Dermatologic Agents

Anesthetics

Aminolevulinic Acid

Xenon

Methyl 5-aminolevulinate

Photosensitizing Agents

Patients who benefit Metvixia application to the vulva to realize fluorescence guided biopsies (Photodynamic diagnosis).

Metvixia is applied with a spatula, in a thick layer, to clinically visible lesions and all over the vulva. After applying the cream, the area will be covered with a bandage which should remain in place for 3 hours. After 3 hours of application, the bandage and the cream will be carefully removed. The application area will be cleaned and then immediately exposed to a continuous spectrum of light at a wavelength of 405 nm by a xenon lamp.

The most fluorescent areas will be identified. Then in white light, the practitioner will perform at least two biopsies under non-topical local anesthesia in the area of application of Metvixia®: one in the fluorescent area and one in the non-fluorescent area.

If there is no fluorescent labeling, two samples will be taken from two different non-fluorescent areas. In the event that all the zone is fluorescent , two samples will be taken from two different fluorescent zones.

Metvixia Topical Cream

Naoual Boujedaini, PhD

Priscillia TOSTI

BOUJEDAINI Naoual, PhD

Lorraine HEJL, MD

This study is a single-center propsective clinical trial to assess the ability of fluorescence techniques to mark high-grade vulvar intraepithelial neoplasias including high-grade vulvar squamous intraepithelial lesions and differentiated vulvar intraepithelial neoplasias following 3 hours Metvixia application.

Evaluation of New Diagnostic Tool Using Fluorescence to Detect High-grade Vulvar Intraepithelial Neoplasia

Evaluation of the Ability of PpIX Fluorescence to Mark High-grade Vulvar Intraepithelial Neoplasia Following the Methyl Aminolevulinate (Metvixia®) Application

Percentage of patients for whom the procedure successfully demonstrated high-grade vulvar intraepithelial neoplasias in fluorescence confirmed by biopsy.

A patient will be considered successful if the presence or absence of fluorescence is consistent with the anatomo-pathological result, that means if her sample in the fluorescent area is positive in pathology and her sample in the non-fluorescent area is negative in anatomo-pathology.

For a patient with no fluorescent labeling, the pathological results of her two samples must be negative for the patient to be considered successful. For a patient where the entire area fluoresces, the anatomo-pathological result of her two samples must be positive for the patient to be considered successful.

The sensitivity will correspond to the number of fluorescent zones among the positive zones in anatomopathology.

The specificity will correspond to the number of non-fluorescent zones among the negative zones in anatomo-pathology.

The fluorescence intensity will be measured by the signal to noise ratio, also called SNR (Signal to Noise Ratio) on photographie

The tolerance of the application will be assessed by the number of grade 3 to 5 toxicity. The toxicity will be evaluated using the CTCAE v5 scale (Common Terminology for Adverse Events). The different grade on this scale is 1 to 5 (1 correspond to a asymptomatic or mild symptome, 2 to moderate toxicity, 3 to severe or medically significant but not immediately life-threatening toxicity, 4 to life-threatening consequences or urgent intervention indicated and 5 to the death related to the toxicity.

Pain will be assessed using a numerical scale from 0 to 10 (0 corresponds to no pain and 10 to maximum pain)

Institut de Cancérologie de Lorraine

Infections

Symptoms and General Pathology

Communicable Diseases

Vulvar Neoplasms

Papillomavirus Infections

Vulvar Diseases

Sexually Transmitted Diseases

Sexually Transmitted Diseases, Viral

Virus Diseases

DNA Virus Infections

Tumor Virus Infections

Disease Attributes

Genital Neoplasms, Female

Urogenital Neoplasms

Vulvar Cancer

Anti-Infective Agents

Fludarabine

Fludarabine phosphate

Vaccines

Aldesleukin

Immunomodulating Agents

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 TCR Cells at escalating doses, followed by aldesleukin

1 x 10 e11 E7 Cells that was determined in Phase I + aldesleukin

T cells genetically engineered with a TCR targeting HPV-16 E7 (E7 TCR) that display specific reactivity against HLA-A2+, HPV-16+ target cells

E7 TCR cells

Following cell infusion the patient receives high-dose bolus aldesleukin, which is dosed to individual patient tolerance. Aldesleukin improves the survival of E7 TCR cells after infusion.

Part of the non-myeloablative lymphocyte-depleting preparative regimen.

Laura A Parsons-Wandell, R.N.

Scott M Norberg, D.O.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

Human papillomavirus (HPV) can cause cervical, throat, anal, and genital cancers. Cancers caused by HPV have a HPV protein called E7 inside of their cells. In this new therapy, researchers take a person s blood, remove certain white blood cells, and insert genes that make them to target cancer cells that have the E7 protein. The genetically changed cells, called E7 TCR cells, are then given back to the person to fight the cancer. Researchers want to see if this can help people.

Objective:

To determine a safe dose and efficacy of E7 TCR cells and whether these cells can help patients.

Eligibility:

Adults ages 18 and older with an HPV-16-associated cancer, including cervical, vulvar, vaginal, penile, anal, or oropharyngeal.

Design:

Participants will list all their medicines.

Participants will have many screening tests, including imaging procedures, heart and lung tests, and lab tests. They will have a large catheter inserted into a vein.

Participants will have leukapheresis. Blood will be removed through a needle in the arm. A machine separates the white blood cells. The rest of the blood is returned through a needle in the other arm.

The cells will be changed in the lab.

Participants will stay in the hospital. Over several days, they will get:

Chemotherapy drugs

E7 TCR cells

Shots or injections to stimulate the cells

Participants will be monitored in the hospital up to 12 days. They will get support medicine and have blood and lab tests.

Participants will have a clinic visit about 40 days after cell infusion. They will have a physical exam, blood work, scans, and maybe x-rays.

Participants will have many follow-up visits with the same procedures. At some visits, they may undergo leukapheresis.

Participants will be followed for 15 years.

Background:

* Metastatic or refractory/recurrent human papillomavirus (HPV)-16+ cancers (cervical, vulvar, vaginal, penile, anal, and oropharyngeal cancers) are incurable and poorly palliated by standard therapies.
* HPV-16+ cancers constitutively express the HPV-16 E7 oncoprotein, which is absent from healthy human tissues.
* Administration of T cell receptor (TCR) gene engineered T cells can induce objective tumor responses in certain malignancies including HPV-16+ cancers.
* T cells genetically engineered with a TCR targeting HPV-16 E7 (E7 TCR) display specific reactivity against HLA-A2+, HPV-16+ target cells.

Objectives:

Phase I Primary Objective

- To determine a safe dose for E7 TCR cells plus aldesleukin for the treatment of metastatic HPV-16+ cancers.

Phase II Primary Objective

-To determine safety and efficacy of E7 TCR cells plus aldesleukin for the treatment of metastatic HPV-16+ cancers.

Eligibility:

* Patients greater than or equal to 18 years old with metastatic or refractory/recurrent HPV-16+ cancer.
* Prior first line systemic therapy is required unless the patient declines standard treatment.
* Patients must be HLA-A\*02:01-positive.

Design:

* This is a phase I/II clinical trial that will test the safety and efficacy of E7 TCR cells.
* All patients will receive a non-myeloablative lymphocyte-depleting preparative regimen of cyclophosphamide and fludarabine followed by a single infusion of E7 TCR cells. Cell infusion will be followed by high-dose aldesleukin.
* Re-enrollment will be allowed for a small number of subjects.

E7 TCR T Cells for Human Papillomavirus-Associated Cancers

A Phase I/II Trial of T Cell Receptor Gene Therapy Targeting HPV-16 E7 for HPV-Associated Cancers

.IPD recorded in the medical record will be shared with intramural investigators upon request.

time from start of treatment to disease progression or death

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
IRX-2 Regimen in Treating Women With Cervical Squamous Intraepithelial Neoplasia 3 or Squamous Vulvar Intraepithelial Neoplasia 3	NCT03267680	Cervical Squamo... Vulvar High Gra...	Cyclophosphamid... Indomethacin IRX-2 Laboratory Biom... Multivitamin Omeprazole Placebo Therapeutic Con...	25 Years -	University of Southern California
Evaluation of New Diagnostic Tool Using Fluorescence to Detect High-grade Vulvar Intraepithelial Neoplasia	NCT05104099	Vulvar Intraepi... Vulvar High Gra... Differentiated ...	Metvixia Topica...	18 Years -	Institut de Cancérologie de Lorraine
IRX-2 Regimen in Treating Women With Cervical Squamous Intraepithelial Neoplasia 3 or Squamous Vulvar Intraepithelial Neoplasia 3	NCT03267680	Cervical Squamo... Vulvar High Gra...	Cyclophosphamid... Indomethacin IRX-2 Laboratory Biom... Multivitamin Omeprazole Placebo Therapeutic Con...	25 Years -	University of Southern California
E7 TCR T Cells for Human Papillomavirus-Associated Cancers	NCT02858310	Papillomavirus ... Cervical Intrae... Carcinoma In Si... Vulvar Neoplasm... Vulvar Diseases	E7 TCR cells Aldesleukin Fludarabine Cyclophosphamid...	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Evaluation of New Diagnostic Tool Using Fluorescence to Detect High-grade Vulvar Intraepithelial Neoplasia	NCT05104099	Vulvar Intraepi... Vulvar High Gra... Differentiated ...	Metvixia Topica...	18 Years -	Institut de Cancérologie de Lorraine

Spots Global Cancer Trial Database for vulvar high grade squamous intraepithelial lesion