E7 TCR T Cells for Human Papillomavirus-Associated Cancers

• ClinicalTrials.gov Identifier: NCT02858310
• Recruitment Status: Recruiting
• First Posted: August 8, 2016
• Last Update Posted: May 25, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Papillomavirus Infections; Cervical Intraepithelial Neoplasia; Carcinoma In Situ; Vulvar Neoplasms; Vulvar Diseases	Biological: E7 TCR cells; Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide	Phase 1; Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 180 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial of T Cell Receptor Gene Therapy Targeting HPV-16 E7 for HPV-Associated Cancers
• Actual Study Start Date: January 27, 2017
• Estimated Primary Completion Date: December 31, 2025
• Estimated Study Completion Date: January 1, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1: Phase I; Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 TCR Cells at escalating doses, followed by aldesleukin	Biological: E7 TCR cells; T cells genetically engineered with a TCR targeting HPV-16 E7 (E7 TCR) that display specific reactivity against HLA-A2+, HPV-16+ target cells; Drug: Aldesleukin; 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.; Drug: Fludarabine; Part of the non-myeloablative lymphocyte-depleting preparative regimen.; Drug: Cyclophosphamide; Part of the non-myeloablative lymphocyte-depleting preparative regimen.
Experimental: Arm 2: Phase II; 1 x 10 e11 E7 Cells that was determined in Phase I + aldesleukin	Biological: E7 TCR cells; T cells genetically engineered with a TCR targeting HPV-16 E7 (E7 TCR) that display specific reactivity against HLA-A2+, HPV-16+ target cells; Drug: Aldesleukin; 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.; Drug: Fludarabine; Part of the non-myeloablative lymphocyte-depleting preparative regimen.; Drug: Cyclophosphamide; Part of the non-myeloablative lymphocyte-depleting preparative regimen.

Outcome Measures

Primary Outcome Measures :

1. Phase II: Determine safety and effficacy of E7 TCR cells plus aldesleukin [ Time Frame: At 12 weeks, every 3 months x 3, every 6 months x 5 years, then as per PI discretion thereafter ]
   Overall response rate (PR +CR)
2. Phase I: Determine a safe dose for E7 TCR cells plus aldesleukin [ Time Frame: 30 days after treatment ]
   Number and type of AEs and/or UPs

Secondary Outcome Measures :

1. To assess progression-free survival [ Time Frame: at time of last patient's progression ]
   time from start of treatment to disease progression or death

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• INCLUSION CRITERIA:

  1. Measurable metastatic or refractory/recurrent HPV-16+ cancer (determined by in situ hybridization (ISH) or a polymerase chain reaction (PCR)-based test).
  2. Patients must be HLA-A*02 by low resolution typing, and HLA-A*02:01 by one of the high resolution type results.
  3. All patients must have received prior first line standard therapy or declined standard therapy.
  4. Patients with three or fewer brain metastases that have been treated with surgery or stereotactic radiosurgery are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month before protocol treatment. Patients with surgically resected brain metastases are eligible.
  5. Greater than or equal to 18 years of age.
  6. Able to understand and sign the Informed Consent Document.
  7. Clinical performance status of ECOG 0 or 1.
  8. Patients of both genders must be willing to practice birth control from the time of enrollment on this study up to four months after treatment. Patients must be willing to undergo testing for HPV-16 prior to becoming pregnant after this period.
  9. Women of childbearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus. Women of childbearing potential are defined as all women except women who are postmenopausal or who have had a hysterectomy. Postmenopausal will be defined as women over the age of 55 who have not had a menstrual period in at least one year. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with E7 TCR transduced PBL, breastfeeding should be discontinued if the mother is treated with E7 TCR transduced PBL. These potential risks may also apply to other agents used in this study.
  10. Serology:
• 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 are less responsive to the experimental treatment and more susceptible to its toxicities.)

• Seronegative for hepatitis B antigen, and seronegative for 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.

  a. Hematology:

• Absolute neutrophil count greater than 1000/mm^3 without the support of

filgrastim.

• WBC greater than or equal to 3000/mm^3
• Platelet count greater than or equal to 100,000/mm^3

• Hemoglobin > 8.0 g/dL

  b. Chemistry:

• Serum ALT/AST less than or equal to 2.5 times the upper limit of normal
• Calculated creatinine clearance (CCr) greater than or equal to 50 mL/min/1.73^2 using the Cockcroft-Gault equation

• Total bilirubin less than or equal to 1.5 mg/dL, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL

  c. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the E7 TCR cells.

Note: Patients may have undergone minor surgical procedures within the past three weeks, as long as all toxicities have recovered to Grade 1 or less.

EXCLUSION CRITERIA:

1. Active systemic infections (for e.g.: requiring anti-infective treatment), coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system, as evidenced by a positive stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, severe obstructive or restrictive pulmonary disease. Patients with abnormal pulmonary function tests but stable obstructive or restrictive pulmonary disease may be eligible.
2. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
3. Concurrent opportunistic infections (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 experimental treatment and more susceptible to its toxicities).
4. Patients with autoimmune diseases such as Crohn s disease, ulcerative colitis, rheumatoid arthritis, autoimmune hepatitis or pancreatitis, and systemic lupus erythematosus. Hypothyroidism, vitiligo and other minor autoimmune disorders are not exclusionary.

5. Patients on immunosuppressive drugs including corticosteroids. With the exception of: intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection)

   -Systemic corticosteroids at physiologic doses 10 mg/day of prednisone or equivalent;

   or,

   -Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

6. History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine or aldesleukin.
7. Patients with a history of coronary revascularization or ischemic symptoms unless patient has a normal cardiac stress test.

8. Documented LVEF of less than or equal to 45% tested. The following patients will undergo cardiac evaluations

   1. Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or
   2. Age greater than or equal to 50 years old
9. Any other condition, which would, in the opinion of the Principal Investigator, indicate that the subject is a poor candidate for the clinical trial or would jeopardize the subject or the integrity of the data obtained.
10. Subjects with baseline screening pulse oxygen level of < 95% on room air will not be eligible. If the underlying cause of hypoxia improves, then they may be reevaluated

Contacts and Locations

Contacts

Contact: Erin W Ferraro, R.N.; (240) 760-6163; erin.ferraro@nih.gov

Contact: Scott M Norberg, D.O.; (301) 275-9668; scott.norberg@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: Scott M Norberg, D.O.; National Cancer Institute (NCI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Draper LM, Kwong ML, Gros A, Stevanovic S, Tran E, Kerkar S, Raffeld M, Rosenberg SA, Hinrichs CS. Targeting of HPV-16+ Epithelial Cancer Cells by TCR Gene Engineered T Cells Directed against E6. Clin Cancer Res. 2015 Oct 1;21(19):4431-9. doi: 10.1158/1078-0432.CCR-14-3341.

Stevanovic S, Draper LM, Langhan MM, Campbell TE, Kwong ML, Wunderlich JR, Dudley ME, Yang JC, Sherry RM, Kammula US, Restifo NP, Rosenberg SA, Hinrichs CS. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol. 2015 May 10;33(14):1543-50. doi: 10.1200/JCO.2014.58.9093. Epub 2015 Mar 30.

Hinrichs CS, Restifo NP. Reassessing target antigens for adoptive T-cell therapy. Nat Biotechnol. 2013 Nov;31(11):999-1008. doi: 10.1038/nbt.2725. Epub 2013 Oct 20.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Nagarsheth NB, Norberg SM, Sinkoe AL, Adhikary S, Meyer TJ, Lack JB, Warner AC, Schweitzer C, Doran SL, Korrapati S, Stevanovic S, Trimble CL, Kanakry JA, Bagheri MH, Ferraro E, Astrow SH, Bot A, Faquin WC, Stroncek D, Gkitsas N, Highfill S, Hinrichs CS. TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat Med. 2021 Mar;27(3):419-425. doi: 10.1038/s41591-020-01225-1. Epub 2021 Feb 8.

Jin BY, Campbell TE, Draper LM, Stevanovic S, Weissbrich B, Yu Z, Restifo NP, Rosenberg SA, Trimble CL, Hinrichs CS. Engineered T cells targeting E7 mediate regression of human papillomavirus cancers in a murine model. JCI Insight. 2018 Apr 19;3(8):e99488. doi: 10.1172/jci.insight.99488. eCollection 2018 Apr 19.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02858310
• Other Study ID Numbers: 160154; 16-C-0154
• First Posted: August 8, 2016
• Last Update Posted: May 25, 2023
• Last Verified: May 4, 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: .IPD recorded in the medical record will be shared with intramural investigators upon request.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

• 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) ):

Immunotherapy; Human Papillomavirus; Vulvar Intraepithelial Neoplasia; Vulvar High Grade Squamous Intraepithelial Lesion; Vaccine; HPV-related Malignancy; HPV-related Carcinoma; HPV-related Cervical Carcinoma; HPV-related Anal Squamous Cell Carcinoma; HPV Positive Oropharyngeal Squamous Cell Cancer

Additional relevant MeSH terms:

Papillomavirus Infections; Carcinoma; Neoplasms; Carcinoma in Situ; Uterine Cervical Dysplasia; Vulvar Neoplasms; Vulvar Diseases; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Precancerous Conditions; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Communicable Diseases; Infections; DNA Virus Infections; Virus Diseases; Tumor Virus Infections; Disease Attributes; Pathologic Processes; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Aldesleukin