Immunotherapy With E7 T Cell Receptor T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT03937791
• Collaborator: (none)
• Enrollment: 1
• Location: 1
• Arm: 1
• Actual Duration (Months): 8.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Background:

Human papillomavirus (HPV) can cause vulvar high-grade squamous intraepithelial lesions (HSIL). Sometimes, this can become cancer. Researchers want to see if T cell therapy can treat vulvar HSIL. In this therapy, a person s immune cells are genetically modified so they can attack the HPV.

Objective:

To test if a personalized immune treatment can cure vulvar HSIL.

Eligibility:

People ages 18 and older with vulvar HSIL that cannot be removed with surgery, or for which surgery has failed

Design:

Participants will be screened with:

Medical history

Physical exam

HPV testing

Venous assessment

Chest x-ray

Heart and pulmonary tests

Participants will have a baseline visit. They may have a vulvar biopsy. Photographs will be taken of their lesions.

Participants will have leukapheresis: Blood is removed from a needle in the arm and circulated through a machine that takes out the white blood cells. The other blood cells are returned through a needle in the other arm. The white blood cells will be used to grow treatment cells.

Participants will receive the treatment through a tube inserted into an arm, neck, or chest vein. They will recover in the hospital for 1 to 2 days. They will have blood tests and take supportive medications.

Participants may have one more treatment.

Participants will have 5 follow-up visits in the first 3 months after treatment. They may have more visits if their disease is growing. Visits will include blood tests. They may include vulvar biopsies or leukapheresis.

Participants will have an annual physical exam for 5 years after treatment that can be done at home or at the National Institutes of Health (NIH). Then they will have an annual phone or email questionnaire for another 10 years....

Condition or Disease	Intervention/Treatment	Phase
Squamous Lntraepithelial Lesions of Vulva; Neoplasms, Squamous Cell; Vulvar HSIL	Biological: E7 T Cell Receptor (TCR)	Phase 2

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 a HPV-16 E7-specific T cell receptor (E7 TCR T cells).

Objective:

-Determine the complete response rate for E7 TCR T cells in the treatment of vulvar HSIL.

Eligibility:

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

• Expression of the human leukocyte antigen (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.

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

Design:

• This is a phase II clinical trial

• Simon minimax two-stage design with initial enrollment of 12 patients and expansion to 16 patients if one or more complete response(s) is/are observed in the initial patients.

• Subjects will receive 1x10^11 E7 TCR T cells

• No conditioning regimen or aldesleukin will be given

• Re-enrollment will be allowed for a small number of subjects.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Immunotherapy With E7 T Cell Receptor T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions
• Actual Study Start Date: Oct 9, 2019
• Actual Primary Completion Date: Jun 22, 2020
• Actual Study Completion Date: Jun 22, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1/1x10^11 E7 T Cell Receptor (TCR) T cells 1x10^11 E7 TCR T cells will be administered intravenously over 20 to 30 minutes on day 0.	Biological: E7 T Cell Receptor (TCR); One dose of E7 TCR T cells (1x10^11 cells) will be administered intravenously over 20 to 30 minutes.

Outcome Measures

Primary Outcome Measures

1. Fraction of Participants With Vulvar High-Grade Squamous Intraepithelial Lesions (HSIL) Who Experience a Complete Response for E7 T-Cell Receptor (TCR) T Cells Treatment [3 months]

   The fraction of patients who experience a complete response. Complete Response is disappearance of all target lesions. No appearance of new lesions.

Secondary Outcome Measures

1. Number of Grade 2 Adverse Events Unlikely Related to Drug in Participants Who Received E7 T-Cell Receptor (TCR) T Cells Administered in a Low Intensity Setting Without Conditioning or Systemic Aldesleukin [30 days following the last dose of study therapy]

   Grade 2 adverse event is moderate.

Other Outcome Measures

1. Number of Participants With Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) [Date treatment consent signed to date off study, approximately 8 months and 6 days.]

   Here is the number of participants with non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

• Patients must have vulvar High-Grade Squamous Intraepithelial Lesions (HSIL) as confirmed by pathology report from a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.

• Vulvar HSIL must be human papillomavirus (HPV)-16+ by a polymerase chain reaction (PCR), Ribonucleic acid (RNA), or in situ hybridization test from a CLIA certified laboratory.

• Patients must have measurable lesion(s) as defined in one or more of the following criteria:

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

• Multifocal or extensive disease for which surgery would result in disfigurement that is not be acceptable to the patient.

• 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).

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

• Patients must have the human leukocyte antigen (HLA)-A*02:01 allele

• Age greater than or equal to18 years.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

• Able to understand and sign the Informed Consent Document.

• 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.

• The effects of E7 T-Cell Receptor (TCR) 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.

• Seronegative for human immunodeficiency virus (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.

• 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 reverse transcription (RT)-PCR and be hepatitis C virus (HCV) RNA negative.

• Must be willing to participate in Gene Therapy Long Term Followup Protocol (20-C-0051), which will follow patients for up to 15 years per Food and Drug Administration (FDA) requirements.

• 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 100,000/mcL

• hemoglobin greater than or equal to 9.0 g/dL

• total bilirubin within 1.5X normal institutional limits except in patients with Gilbert's Syndrome who must have a total bilirubin < 3.0 mg/dL

• Aspartate Aminotransferase (AST)/Serum glutamic-oxaloacetic transaminase(SGOT)/Alanine Aminotransferase (ALT)/Serum glutamic pyruvic transaminase,(SGPT) Serum ALT/AST < 3X upper limit of normal (ULN)

• creatinine < 1.5X baseline, < 1.5X ULN OR

• creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal (by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation)

EXCLUSION CRITERIA:

• Patients who are receiving any other investigational agents

• Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with E7 TCR, breastfeeding should be discontinued if the mother is treated with E7 TCR. These potential risks may also apply to other agents used in this study.

• 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.

• 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 maybe less responsive to the treatment.

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

• Cardiac stress test and pulmonary function tests maybe required for patients with a clinical history of significat cardiopulmonary disease. Patients with active cardiac ischemia or severe chronic obstructive pulmonary disease are not eligible.

• Patients with any active invasive cancer are not eligible.

• Patients with vulvar HSIL that is not HPV-16+ or is associated with multiple types of high-risk HPV at the time of eligibility assessment are not eligible.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Scott Norberg, D.O., National Cancer Institute (NCI)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 27, 2020
• Informed Consent Form: Cohort Screening Consent - Jun 4, 2020
• Informed Consent Form: Cohort Treatment Consent - Jun 4, 2020

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

None provided.

• Responsible Party: Scott Norberg, D.O., Principal Investigator, National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT03937791
• Other Study ID Numbers: 190091; 19-C-0091
• First Posted: May 6, 2019
• Last Update Posted: Apr 13, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Scott Norberg, D.O., Principal Investigator, National Cancer Institute (NCI): Human Papilloma Virus (HPV) Type 16; Retroviral Vector Supernatant; Leukapheresis; T Cell Receptor; Premalignant Epithelial Lesion
• Additional relevant MeSH terms: Neoplasms, Squamous Cell

Study Results

Participant Flow

Arm/Group Title	Arm 1/1x10^11 E7 T Cell Receptor (TCR) T Cells
Arm/Group Description	1x10^11 E7 TCR T cells will be administered intravenously over 20 to 30 minutes on day 0. E7 T Cell Receptor (TCR): One dose of E7 TCR T cells (1x10^11 cells) will be administered intravenously over 20 to 30 minutes.
Period Title: Overall Study
STARTED	1
COMPLETED	1
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Arm 1/1x10^11 E7 T Cell Receptor (TCR) T Cells
Arm/Group Description	1x10^11 E7 TCR T cells will be administered intravenously over 20 to 30 minutes on day 0. E7 T Cell Receptor (TCR): One dose of E7 TCR T cells (1x10^11 cells) will be administered intravenously over 20 to 30 minutes.
Overall Participants	1
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.2 (0)
Sex: Female, Male (Count of Participants)
Female	1 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	1 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	1 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	1 100%

Outcome Measures

1. Primary Outcome

Title	Fraction of Participants With Vulvar High-Grade Squamous Intraepithelial Lesions (HSIL) Who Experience a Complete Response for E7 T-Cell Receptor (TCR) T Cells Treatment
Description	The fraction of patients who experience a complete response. Complete Response is disappearance of all target lesions. No appearance of new lesions.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1/1x10^11 E7 T Cell Receptor (TCR) T Cells
Arm/Group Description	1x10^11 E7 TCR T cells will be administered intravenously over 20 to 30 minutes on day 0. E7 T Cell Receptor (TCR): One dose of E7 TCR T cells (1x10^11 cells) will be administered intravenously over 20 to 30 minutes.
Measure Participants	1
Number (95% Confidence Interval) [Proportion of participants]	0 0%

2. Secondary Outcome

Title	Number of Grade 2 Adverse Events Unlikely Related to Drug in Participants Who Received E7 T-Cell Receptor (TCR) T Cells Administered in a Low Intensity Setting Without Conditioning or Systemic Aldesleukin
Description	Grade 2 adverse event is moderate.
Time Frame	30 days following the last dose of study therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1/1x10^11 E7 T Cell Receptor (TCR) T Cells
Arm/Group Description	1x10^11 E7 TCR T cells will be administered intravenously over 20 to 30 minutes on day 0. E7 T Cell Receptor (TCR): One dose of E7 TCR T cells (1x10^11 cells) will be administered intravenously over 20 to 30 minutes.
Measure Participants	1
Number [adverse events]	1

3. Other Pre-specified Outcome

Title	Number of Participants With Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
Description	Here is the number of participants with non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence.
Time Frame	Date treatment consent signed to date off study, approximately 8 months and 6 days.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1/1x10^11 E7 T Cell Receptor (TCR) T Cells
Arm/Group Description	1x10^11 E7 TCR T cells will be administered intravenously over 20 to 30 minutes on day 0. E7 T Cell Receptor (TCR): One dose of E7 TCR T cells (1x10^11 cells) will be administered intravenously over 20 to 30 minutes.
Measure Participants	1
Count of Participants [Participants]	1 100%

Adverse Events

Time Frame	Date treatment consent signed to date off study, approximately 8 months and 6 days.
Arm/Group Title	Arm 1/1x10^11 E7 T Cell Receptor (TCR) T Cells
Arm/Group Description	1x10^11 E7 TCR T cells will be administered intravenously over 20 to 30 minutes on day 0. E7 T Cell Receptor (TCR): One dose of E7 TCR T cells (1x10^11 cells) will be administered intravenously over 20 to 30 minutes.
All Cause Mortality
	Arm 1/1x10^11 E7 T Cell Receptor (TCR) T Cells
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Serious Adverse Events
	Arm 1/1x10^11 E7 T Cell Receptor (TCR) T Cells
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Other (Not Including Serious) Adverse Events
	Arm 1/1x10^11 E7 T Cell Receptor (TCR) T Cells
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Reproductive system and breast disorders
Vaginal pain	1/1 (100%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.