E7 TCR T Cell Induction Immunotherapy for Stage IIB-IVA Cervical Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT04476251
• Collaborator: (none)
• Enrollment: 1
• Location: 1
• Arm: 1
• Actual Duration (Months): 8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Background:

More than 12,000 cases of cervical cancer are diagnosed in the United States each year. A new therapy has been developed that involves taking white blood cells from a person, genetically modifying the cells in a lab so they recognize cancer, and then giving the cells back to the person. Researchers want to see if this therapy can help people with cervical cancer.

Objective:

To find out if people with Stage IIB-IVA cervical cancer can safely be given E7 T-cell receptor (TCR) T cells before they get standard treatment.

Eligibility:

People age 18 and older who have Stage IIB-IVA cervical cancer

Design:

Participants will be screened under a separate protocol. Tests will include:

• Physical exam

• Medicine review

• Blood tests

• Pregnancy test (if needed)

• Vein assessment

• Tumor sample or biopsy

• Electrocardiogram (to record the hearts electrical activity)

• Imaging scans, x-rays, and/or endoscopy

• Heart and/or lung tests.

Some screening tests will be repeated during the study.

Participants will undergo leukapheresis. For this, blood is removed through a needle in the arm. A machine removes the white blood cells. The rest of the blood is returned through a needle in the other arm. Participants may need to have a large catheter inserted into a vein.

Participants will stay at the hospital for 2-3 weeks. They will get chemotherapy drugs. They will get the E7 TCR T cells as an intravenous infusion. They will get the drug aldesleukin.

Participants will visit the National Institutes of Health (NIH) 3 and 6 weeks after treatment. They will be contacted yearly for 5 years. They will be asked to participate in long-term follow-up for 15 years....

Condition or Disease	Intervention/Treatment	Phase
Uterine Cervical Neoplasms	Biological: E7 T-Cell Receptor (TCR)	Early Phase 1

Detailed Description

Background:

• Cervical cancer is the third most common cause of death among women with gynecologic cancers in the United States. Worldwide, cervical cancer accounts for nearly 300,000 deaths annually.

• Virtually all cases of cervical cancer result from chronic infection with high-risk human papillomavirus (HPV), the most common type being HPV16.

• The treatment of locally advanced cervical cancer consists of chemoradiation +/- extended field radiation therapy. Participants with International Federation of Gynecology and Obstetrics (FIGO) (revised 2018) stage III-IVA have the worse prognosis with approximately 50% of the participants dying from their disease within 5 years.

• Induction chemotherapy is an active area of study in this type of cancer. The aim of induction therapy is to reduce the risk of disease recurrence and improve overall survival.

• E7 T-cell receptor (TCR) T cells, administered as a single infusion, have demonstrated safety and clinical activity in advanced, treatment-refractory metastatic HPV+ cancers.

Objectives:

-To determine the feasibility of induction E7 TCR T cell therapy for FIGO (2018) stage IIB-IVA, HPV16+ cervical cancer

Eligibility:

• Participants greater than or equal to 18 years old with FIGO (2018) stage IIB-IVA cervical cancer.

• The cancer must be human papillomavirus 16 (HPV16+) and participant must be HLA-A*02:01+.

• Participants must be treatment-naive (i.e., no prior local or systemic treatment, including radiation; prior loop electrosurgical excision procedure (LEEP) procedure or cone biopsy is allowed).

Design:

• This is a single arm, pilot study, testing the feasibility of induction E7 TCR T cell therapy.

• Participants will receive a conditioning regimen of cyclophosphamide and fludarabine, a single infusion of E7 TCR T cells, and systemic aldesleukin.

• Participants will be referred for standard of care definitive therapy (i.e., chemoradiation +/- extended field radiation therapy) within 6 weeks after infusion of E7 TCR T cells.

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 Pilot Study of E7 TCR T Cell Induction Immunotherapy for Stage IIB-IVA Cervical Cancer
• Actual Study Start Date: Jan 14, 2021
• Actual Primary Completion Date: Sep 15, 2021
• Actual Study Completion Date: Sep 15, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1/E7 T-Cell Receptor (TCR) T Cell Therapy E7 TCR T Cell Therapy	Biological: E7 T-Cell Receptor (TCR); Patients will receive up to 3x10^10 E7 T-Cell Receptor (TCR) T cells (i.e. TCR+ cells).

Outcome Measures

Primary Outcome Measures

1. The Fraction of Participants for Whom E7 T-Cell Receptor (TCR) Induction Therapy is Feasible in Participants With Cervical Cancer [6 months]

   The Fraction of participants for whom E7 T-Cell Receptor (TCR) induction therapy is feasible in participants with cervical cancer

Secondary Outcome Measures

1. Fraction of Participants With Relapse-free Survival at 2 Years and 5 Years Following Definitive Standard of Care Therapy [2 yrs and 5 yrs]

   Fraction of participants with relapse-free survival at 2 years and 5 years estimated from a Kaplan-Meier curve of relapsed free survival following definitive standard of care therapy who achieve a success. Relapsed free survival is defined as the time from date on study to date of relapse of disease.

2. Fraction of Participants With Grade 1-5 Adverse Events [1 year]

   To evaluate the safety of E7 induction therapy, the types and grades of toxicity obtained will be reported. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse event.

3. Percentage of E7 T-Cell Receptor (TCR)T Cells Following Completion of Chemoradiation [1 year]

   Percentage of E7 T-Cell Receptor (TCR)T cells following completion of chemoradiation

4. Fraction of Participants Who Achieve an Objective Response (Partial Response + Complete Response) Following E7 T-Cell Receptor (TCR) T Cell Induction Therapy [1 year]

   Fraction of participants who achieve an objective response (Partial Response + Complete Response) following E7 induction therapy will be reported. Response may be assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete Response is disappearance of all target lesions. Partial Response is at least a 30% decrease in the sum of the diameters of target lesion; and/or Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST). Complete Metabolic Response is complete resolution of F-fluorodeoxyglucose (FDG) uptake in all lesions, and Partial Metabolic Response is ≥ 30% reduction of the SUL (lean body mass corrected standard uptake value) peak and an absolute drop of 0.8 SULpeak units.

Other Outcome Measures

1. Number of Participants With Serious and 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 20 days.]

   Here is the number of participants with serious and 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. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Eligibility Criteria

Criteria

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

-INCLUSION CRITERIA:

1. Participants with histologically or cytologically confirmed carcinoma of the cervix that has not been treated, with clinical staging as follows:

• Lead-in safety cohort: FIGO (International Federation of Gynecology and Obstetrics) stage IIIC-IVA (2018 International FIGO Staging System)

• After lead-in safety cohort: FIGO stage IIB-IVA (2018 International FIGO Staging System)

1. Human papillomavirus 16 (HPV16+) tumor and HLA-A02:01+ Human leukocyte antigen (HLA) type. Note: HLA-A02 is also acceptable for enrollment but not for treatment.

2. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) (if not eligible by RECIST 1.1).

3. Age 18 years. Because no dosing or adverse event data are currently available on the use of E7 TCR T cells in participants <18 years of age, children are excluded from this study. Note: This age range is consistent with the age of participants with the disease being studied.

4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

5. Women of child-bearing potential must have a negative pregnancy test because E7 TCR T cells have unknown potential for teratogenic or abortifacient effects. Women of child- bearing potential are defined as all women who are not post-menopausal or who have not had a hysterectomy. Note: Postmenopausal will be defined in this study as women over the age of 55 who have not had a menstrual period in at least 1 year.

6. The effects of E7 TCR T cells on the developing human fetus are unknown. For this reason and because the chemotherapy agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (e.g., intrauterine device, hormonal or barrier method of birth control; abstinence; tubal ligation or vasectomy) prior to study entry and for four months after treatment. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.

7. Seronegative for HIV (human immunodeficiency virus) antibody. The experimental treatment being evaluated in this protocol depends on an intact immune system. Participants who are HIV seropositive can have decreased immune-competence and thus be less responsive to the experimental treatment.

8. Seronegative for hepatitis B antigen and hepatitis C antibody. If hepatitis C antibody test is positive, then the participant must be tested for the presence of antigen by Reverse transcription polymerase chain reaction (RT-PCR) and be hepatitis C Virus (HCV) ribonucleic acid (RNA) negative.

9. Must be willing to participate in Gene Therapy Long Term Follow up Protocol (20C0051), which will follow participants for up to 15 years per Food and Drug Administration (FDA) requirements.

10. Participants must have organ and marrow function as defined below:

• leukocytes >=3,000/mcL

• absolute neutrophil count >=1,500/mcL

• platelets >=100,000/mcL

• hemoglobin >=9.0 g/dL

• total bilirubin within normal institutional limits except in participants 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 glutamate-pyruvate transaminase (SGPT) Serum ALT/AST < 2.5X ULN

• creatinine clearance Calculated creatinine clearance (CrCl) >=50 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal (by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation)

1. Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

1. Previous treatment for invasive cervical cancer including:

• Chemotherapy or other systemic treatments

• Radiation therapy

• Hysterectomy (prior LEEP procedure or cone biopsy is allowed)

1. Participants who are receiving any other investigational agents.

2. History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in study.

3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations at the time of treatment that would limit compliance with study requirements.

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

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

6. Participants on immunosuppressive drugs including corticosteroids.

7. Participants with autoimmune diseases such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, autoimmune hepatitis, autoimmune pancreatitis, or systemic lupus erythematosus. Hypothyroidism, vitiligo and other minor autoimmune disorders are not exclusionary.

8. Participants with a second invasive malignancy requiring treatment within the last 2 years are not eligible with the following exceptions:

• Ductal carcinoma in situ (DCIS) of the breast

• Cutaneous skin cancers requiring only local excision

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 M Norberg, D.O., National Cancer Institute (NCI)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 4, 2020
• Informed Consent Form: Screening Consent - Jan 2, 2021
• Informed Consent Form: Affected Patient Consent - Jan 2, 2021

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: NCT04476251
• Other Study ID Numbers: 200116; 20-C-0116
• First Posted: Jul 20, 2020
• Last Update Posted: Dec 15, 2021
• Last Verified: Dec 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): T Cell Receptor; Immunotherapy; Aldesleukin; Cyclophosphamide; Fludarabine
• Additional relevant MeSH terms: Uterine Cervical Neoplasms

Study Results

Participant Flow

Arm/Group Title	Arm 1/E7 T-Cell Receptor (TCR) T Cell Therapy
Arm/Group Description	E7 TCR T Cell Therapy E7 TCR: Patients will receive up to 3x10^10 E7 T-Cell Receptor (TCR) T cells (i.e. TCR+ cells).
Period Title: Overall Study
STARTED	1
COMPLETED	0
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Arm 1/E7 T-Cell Receptor (TCR) T Cell Therapy
Arm/Group Description	E7 TCR T Cell Therapy E7 TCR: Patients will receive up to 3x10^10 E7 T-Cell Receptor (TCR) T cells (i.e. TCR+ cells).
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]	18 (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	1 100%
White	0 0%
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	The Fraction of Participants for Whom E7 T-Cell Receptor (TCR) Induction Therapy is Feasible in Participants With Cervical Cancer
Description	The Fraction of participants for whom E7 T-Cell Receptor (TCR) induction therapy is feasible in participants with cervical cancer
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

This outcome measure was not done due to multiple logistical challenges. One participant was enrolled but not treated.

Arm/Group Title	Arm 1/E7 T-Cell Receptor (TCR) T Cell Therapy
Arm/Group Description	E7 TCR T Cell Therapy E7 TCR: Patients will receive up to 3x10^10 E7 T-Cell Receptor (TCR) T cells (i.e. TCR+ cells).
Measure Participants	0

2. Secondary Outcome

Title	Fraction of Participants With Relapse-free Survival at 2 Years and 5 Years Following Definitive Standard of Care Therapy
Description	Fraction of participants with relapse-free survival at 2 years and 5 years estimated from a Kaplan-Meier curve of relapsed free survival following definitive standard of care therapy who achieve a success. Relapsed free survival is defined as the time from date on study to date of relapse of disease.
Time Frame	2 yrs and 5 yrs

Outcome Measure Data

Analysis Population Description

This outcome measure was not done due to multiple logistical challenges. One participant was enrolled but not treated.

Arm/Group Title	Arm 1/E7 T-Cell Receptor (TCR) T Cell Therapy
Arm/Group Description	E7 TCR T Cell Therapy E7 TCR: Patients will receive up to 3x10^10 E7 T-Cell Receptor (TCR) T cells (i.e. TCR+ cells).
Measure Participants	0

3. Secondary Outcome

Title	Fraction of Participants With Grade 1-5 Adverse Events
Description	To evaluate the safety of E7 induction therapy, the types and grades of toxicity obtained will be reported. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse event.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

This outcome measure was not done due to multiple logistical challenges. One participant was enrolled but not treated.

Arm/Group Title	Arm 1/E7 T-Cell Receptor (TCR) T Cell Therapy
Arm/Group Description	E7 TCR T Cell Therapy E7 TCR: Patients will receive up to 3x10^10 E7 T-Cell Receptor (TCR) T cells (i.e. TCR+ cells).
Measure Participants	0

4. Secondary Outcome

Title	Percentage of E7 T-Cell Receptor (TCR)T Cells Following Completion of Chemoradiation
Description	Percentage of E7 T-Cell Receptor (TCR)T cells following completion of chemoradiation
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

This outcome measure was not done due to multiple logistical challenges. One participant was enrolled but not treated.

Arm/Group Title	Arm 1/E7 T-Cell Receptor (TCR) T Cell Therapy
Arm/Group Description	E7 TCR T Cell Therapy E7 TCR: Patients will receive up to 3x10^10 E7 T-Cell Receptor (TCR) T cells (i.e. TCR+ cells).
Measure Participants	0

5. Secondary Outcome

Title	Fraction of Participants Who Achieve an Objective Response (Partial Response + Complete Response) Following E7 T-Cell Receptor (TCR) T Cell Induction Therapy
Description	Fraction of participants who achieve an objective response (Partial Response + Complete Response) following E7 induction therapy will be reported. Response may be assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete Response is disappearance of all target lesions. Partial Response is at least a 30% decrease in the sum of the diameters of target lesion; and/or Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST). Complete Metabolic Response is complete resolution of F-fluorodeoxyglucose (FDG) uptake in all lesions, and Partial Metabolic Response is ≥ 30% reduction of the SUL (lean body mass corrected standard uptake value) peak and an absolute drop of 0.8 SULpeak units.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

This outcome measure was not done due to multiple logistical challenges. One participant was enrolled but not treated.

Arm/Group Title	Arm 1/E7 T-Cell Receptor (TCR) T Cell Therapy
Arm/Group Description	E7 TCR T Cell Therapy E7 TCR: Patients will receive up to 3x10^10 E7 T-Cell Receptor (TCR) T cells (i.e. TCR+ cells).
Measure Participants	0

6. Other Pre-specified Outcome

Title	Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
Description	Here is the number of participants with serious and 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. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time Frame	Date treatment consent signed to date off study, approximately 20 days.

Outcome Measure Data

Analysis Population Description

This outcome measure was not done due to multiple logistical challenges. One participant was enrolled but not treated.

Arm/Group Title	Arm 1/E7 T-Cell Receptor (TCR) T Cell Therapy
Arm/Group Description	E7 TCR T Cell Therapy E7 TCR: Patients will receive up to 3x10^10 E7 T-Cell Receptor (TCR) T cells (i.e. TCR+ cells).
Measure Participants	0

Adverse Events

Time Frame	Date treatment consent signed to date off study, approximately 20 days.
Arm/Group Title	Arm 1/E7 T-Cell Receptor (TCR) T Cell Therapy
Arm/Group Description	E7 TCR T Cell Therapy E7 TCR: Patients will receive up to 3x10^10 E7 T-Cell Receptor (TCR) T cells (i.e. TCR+ cells).
All Cause Mortality
	Arm 1/E7 T-Cell Receptor (TCR) T Cell Therapy
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Serious Adverse Events
	Arm 1/E7 T-Cell Receptor (TCR) T Cell Therapy
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Other (Not Including Serious) Adverse Events
	Arm 1/E7 T-Cell Receptor (TCR) T Cell Therapy
	Affected / at Risk (%)	# Events
Total	0/1 (0%)

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.