Clinical Trials /

Immunotherapy With E6 T Cell Receptor (TCR) T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions

NCT03197025

Description:

Background: Vulvar high-grade squamous intraepithelial lesion (HSIL) is caused by infection of the vulva with human papillomavirus (HPV). In a small percentage of cases, vulvar HSIL can turn into cancer. The risk of cancer can be reduced by treating HSIL. A personalized immune treatment might rid the body of HPV infection and thereby cure vulvar HSIL. The immune treatment in this study is called T cell therapy. The cells are E6 TCR T cells. Participants will also get aldesleukin (IL-2) to help the cells last longer. Objective: To find a safe dose of E6 TCR T cells combined with aldesleukin to use in people with vulvar HSIL. Eligibility: Design: Participants will be screened with: Physical exam Medical history Blood, lab, and pregnancy tests Heart tests Chest x-ray Sample of tissue taken from the vulva (biopsy). Participants will have leukapheresis. Blood will be removed by a needle in one arm. A machine removes white blood cells from the blood. The rest of the blood is returned by needle in the other arm. The white blood cells will be changed into E6 TCR T cells and grown in a lab. About 3 weeks later, participants will be admitted to the hospital for about 5 days. They will get the cells through a tube placed in a vein. They will get IL-2 the same way. Participants will recover 1-3 days in the hospital. They will be monitored closely. They will have blood and lab tests. Participants will have follow-up visits with lab tests and a physical exam every few months for 5 years. At some visits they will also have leukapheresis, blood tests, or vulvar biopsy.

Related Conditions:
  • Vulvar High Grade Squamous Intraepithelial Lesion
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Immunotherapy With E6 T Cell Receptor (TCR) T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions
  • Official Title: A Phase I Study of Immunotherapy With E6 T Cell Receptor T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions

Clinical Trial IDs

  • ORG STUDY ID: 170116
  • SECONDARY ID: 17-C-0116
  • NCT ID: NCT03197025

Conditions

  • Human Papillomavirus
  • HPV-16
  • High Grade Squamous Intraepithelial Lesion

Interventions

DrugSynonymsArms
AldesleukinMTD
E6 TCRMTD

Purpose

Background: Vulvar high-grade squamous intraepithelial lesion (HSIL) is caused by infection of the vulva with human papillomavirus (HPV). In a small percentage of cases, vulvar HSIL can turn into cancer. The risk of cancer can be reduced by treating HSIL. A personalized immune treatment might rid the body of HPV infection and thereby cure vulvar HSIL. The immune treatment in this study is called T cell therapy. The cells are E6 TCR T cells. Participants will also get aldesleukin (IL-2) to help the cells last longer. Objective: To find a safe dose of E6 TCR T cells combined with aldesleukin to use in people with vulvar HSIL. Eligibility: Design: Participants will be screened with: Physical exam Medical history Blood, lab, and pregnancy tests Heart tests Chest x-ray Sample of tissue taken from the vulva (biopsy). Participants will have leukapheresis. Blood will be removed by a needle in one arm. A machine removes white blood cells from the blood. The rest of the blood is returned by needle in the other arm. The white blood cells will be changed into E6 TCR T cells and grown in a lab. About 3 weeks later, participants will be admitted to the hospital for about 5 days. They will get the cells through a tube placed in a vein. They will get IL-2 the same way. Participants will recover 1-3 days in the hospital. They will be monitored closely. They will have blood and lab tests. Participants will have follow-up visits with lab tests and a physical exam every few months for 5 years. At some visits they will also have leukapheresis, blood tests, or vulvar biopsy....

Detailed Description

      Background:

        -  Vulvar high-grade squamous intraepithelial lesion (HSIL) is a premalignant epithelial
           lesion that is frequently multifocal and/or recurrent.

        -  The primary treatment is surgery, which may result in disfigurement and compromise of
           the urethra, anus, or clitoris. Recurrence after surgery is common and primarily
           treated with additional surgery.

        -  Vulvar HSIL is caused by chronic infection with the human papillomavirus (HPV) type 16
           infection. In this clinical trial the HPV-16 infection is targeted with a single
           infusion of autologous T cells that have been genetically engineered to express an
           HPV-16 E6-specific

      T cell receptor (E6 TCR T cells).

      Objective:

      -Determine the safety of E6 TCR T cells for the treatment of vulvar HSIL.

      Eligibility:

        -  Histologically confirmed diagnosis of HPV-16+ vulvar HSIL.

        -  Expression of the HLA-A2*02:01 allele.

        -  Measurable lesion(s) that are recurrent or cannot be resected with acceptable cosmetic
           or functional results.

        -  Age greater than or equal to 18 years old and less than or equal to 60 years old.

        -  Eastern Oncology Cooperative Group Performance Score of 0 or 1.

      Design:

        -  This is a phase I clinical trial with a 3+3 dose escalation design.

        -  Subjects will receive E6 TCR T cells followed by up to two doses of aldesleukin 720,000
           IU/kg IV.

        -  No conditioning regimen will be given, aldesleukin will be capped at a maximum of two
           doses, and E6 TCR T cell dosing will begin at dose level -1 from the previously
           determined safe dose.
    

Trial Arms

NameTypeDescriptionInterventions
MTDExperimentalPatients will receive infusion of E6 TCR cells followed by a maximum of two doses of Aldesleukin
  • Aldesleukin
Safety/Clinical ResponseExperimentalPatients will receive infusion of E6 TCR cells followed by a maximum of two doses of Aldesleukin
  • Aldesleukin

Eligibility Criteria

        -  INCLUSION CRITIERA:

               1. Patients must have vulvar HSIL as confirmed by pathology report from a
                  CLIA-certified laboratory.

               2. Vulvar HSIL must be HPV-16+ by a PCR, RNA, or in situ hybridization test from a
                  CLIA certified laboratory.

               3. Patients must have measurable lesion(s) as defined in section 6.3.2 and one or
                  more of the following criteria:

                    1. Failure of surgery to control disease (i.e. positive margins or recurrence
                       of HSIL after surgery).

                    2. Multifocal or extensive disease for which surgery would result in major
                       deformity that is not be acceptable to the patient.

                    3. Disease for which surgery would have a risk of functional impairment that
                       is not be acceptable to the patient (i.e. involve partial or complete
                       excision of the clitoris, anus, vagina, or urethra).

               4. Patients may have received any previous therapy, including surgical excision,
                  but must have histologically documented recurrence on new biopsy and a
                  measurable lesion that meets the above criteria.

               5. The presence of disease that can be biopsied for research purposes is not an
                  inclusion criterion.

               6. Patients must have the HLA-A*02:01 allele

               7. Age >18 years and less than or equal to 60 years. As age increases, the ability
                  to tolerate the toxicities of aldesleukin decreases, so the patient population
                  for this study will include up to and including 60 years of age to increase
                  safety.

               8. ECOG performance status of 0-1. Able to understand and sign the Informed Consent
                  Document.

               9. Women of child-bearing potential must have a negative pregnancy test. Women of
                  child-bearing potential are defined as all women who are not post-menopausal or
                  who have not had a hysterectomy. Postmenopausal will be defined as women over
                  the age of 55 who have not had a menstrual period in at least 1 year.

              10. The effects of E6TCR T Cells on the developing human fetus are unknown. For this
                  reason, women of child-bearing potential must agree to use adequate
                  contraception (hormonal or barrier method of birth control; abstinence) prior to
                  study entry and for the duration of study participation. Should a woman become
                  pregnant or suspect she is pregnant while she is participating in this study,
                  she should inform her treating physician immediately.

              11. Seronegative for HIV antibody. The experimental treatment being evaluated in
                  this protocol depends on an intact immune system. Patients who are HIV
                  seropositive can have decreased immune-competence and thus be less responsive to
                  the experimental

                  treatment.

              12. Seronegative for hepatitis B antigen and hepatitis C antibody. If hepatitis C
                  antibody test is positive, then the patient must be tested for the presence of
                  antigen by RT-PCR and be HCV RNA negative.

              13. Must be willing to participate in Gene Therapy Long Term Followup Protocol
                  (15-C-0141), which will follow patients for up to 15 years per Food and Drug
                  Administration (FDA) requirements.

              14. Patients must have normal organ and marrow function as defined below:

          -  leukocytes >3,000/mcL

          -  absolute neutrophil count >1,000/mcL

          -  platelets >150,000/mcL

          -  hemoglobin >10.0 g/dL

          -  total bilirubin within normal institutional limits except in patients with Gilbert s
             Syndrome who must have a total bilirubin < 3.0 mg/dL

          -  AST(SGOT)/ALT(SGPT) wnl

          -  creatinine wnl

        OR

        -creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels above
        institutional normal (by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
        equation)

        EXCLUSION CRITERIA:

          1. Patients who are receiving any other investigational agents

          2. Because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with E6 TCR, breastfeeding should be
             discontinued if the mother is treated with E6 TCR. These potential risks may also
             apply to other agents used in this study.

          3. Uncontrolled intercurrent illness including, but not limited to, any ongoing or
             active infection (e.g. requiring anti-infective therapy), coagulation disorders,
             cardiovascular disorders, respiratory disorders, cancer, or psychiatric
             illness/social situations (within the last six months) that would limit compliance
             with study requirements.

          4. Any form of systemic immunodeficiency, including acquired deficiency such as HIV or
             primary immunodeficiency such as Severe Combined Immunodeficiency Disease. The
             experimental treatment being evaluated in this protocol depends on an intact immune
             system. Patients who have decreased immune competence may be less responsive to the
             treatment.

          5. Concurrent systemic steroid therapy if greater than the equivalent of 5 mg prednisone
             PO daily. Patients previously on steroids must be off steroids for four weeks prior
             to treatment.

          6. Any history of clinically significant cardiac arrhythmia, coronary revascularization,
             ischemic symptoms, or previously documented LVEF of less than or equal to 45%. A
             cardiac stress test is required for all patients greater than 50 years old. A cardiac
             stress test may also be performed for any clinical concern. Patients with cardiac
             ischemia are not eligible.

          7. Patients with any active invasive cancer are not eligible.

          8. Patients vulvar HSIL that is not HPV-16+ or is associated with multiple types of
             high-risk HPV are not eligible.
      
Maximum Eligible Age:60 Years
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:To determine the MTD of E6 TCR T cells for the treatment of vulvarHSIL.
Time Frame:weekly, monthly, annually.
Safety Issue:
Description:

Secondary Outcome Measures

Measure:To assess clinical responses in subjects treated with E6 TCR T cellsfor vulvar HSIL
Time Frame:weekly, monthly, annually
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • HPV-16
  • premalignancy
  • T Cell Therapy

Last Updated

June 22, 2017