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

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ClinicalTrials.gov Identifier: NCT03197025
Recruitment Status : Recruiting
First Posted : June 23, 2017
Last Update Posted : August 6, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Human Papillomavirus HPV-16 High Grade Squamous Intraepithelial Lesion Drug: Aldesleukin Biological: E6 TCR Phase 1

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 65 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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Immunotherapy With E6 T Cell Receptor T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions
Actual Study Start Date : January 9, 2018
Estimated Primary Completion Date : February 5, 2020
Estimated Study Completion Date : February 5, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Aldesleukin

Arm Intervention/treatment
Experimental: MTD
Patients will receive infusion of E6 TCR cells followed by a maximum of two doses of Aldesleukin
Drug: Aldesleukin
Aldesleukin 720,000 IU/kg (based on total body weight) IV infused over 15 minutes approximately every 12 hours for a maximum of two doses.

Biological: E6 TCR
On day 0, the E6 TCR cells will be administered one time, intravenously over 20 to 30 minutes

Experimental: Safety/Clinical Response
Patients will receive infusion of E6 TCR cells followed by a maximum of two doses of Aldesleukin
Drug: Aldesleukin
Aldesleukin 720,000 IU/kg (based on total body weight) IV infused over 15 minutes approximately every 12 hours for a maximum of two doses.

Biological: E6 TCR
On day 0, the E6 TCR cells will be administered one time, intravenously over 20 to 30 minutes




Primary Outcome Measures :
  1. To determine the MTD of E6 TCR T cells for the treatment of vulvarHSIL. [ Time Frame: weekly, monthly, annually. ]

Secondary Outcome Measures :
  1. To assess clinical responses in subjects treated with E6 TCR T cellsfor vulvar HSIL [ Time Frame: weekly, monthly, annually ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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 greater than or equal to 18 years and less than or equal to 65 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 greater than or equal to 3,000/mcL
  • absolute neutrophil count greater than or equal to 1,000/mcL
  • platelets greater than or equal to 150,000/mcL
  • hemoglobin greater than or equal to 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) Serum ALT/AST < 3 times ULN
  • creatinine less than 1.5 times baseline, < 1.5 times ULN

OR

-creatinine clearance less than or equal to 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03197025


Contacts
Contact: Erin W Ferraro, R.N. (833) 815-0387 erin.ferraro@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Christian S Hinrichs, M.D. National Cancer Institute (NCI)

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03197025     History of Changes
Other Study ID Numbers: 170116
17-C-0116
First Posted: June 23, 2017    Key Record Dates
Last Update Posted: August 6, 2018
Last Verified: August 1, 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
HPV-16
premalignancy
T Cell Therapy

Additional relevant MeSH terms:
Squamous Intraepithelial Lesions of the Cervix
Uterine Cervical Dysplasia
Precancerous Conditions
Neoplasms
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female
Aldesleukin
Interleukin-2
Antineoplastic Agents
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs