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E7 TCR T Cells for Human Papillomavirus-Associated Cancers

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ClinicalTrials.gov Identifier: NCT02858310
Recruitment Status : Recruiting
First Posted : August 8, 2016
Last Update Posted : August 31, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

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 18-66 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 and less than or equal to 66 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 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 With or Without PD-1 Blockade for HPV-Associated Cancers
Actual Study Start Date : January 27, 2017
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : January 1, 2026

Resource links provided by the National Library of Medicine


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 Cellsthat 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.




Primary Outcome Measures :
  1. Phase I: Determine a safe dose for E7 TCR cells plus aldesleukin with or without pembrolizumab [ Time Frame: 10 days after treatment ]
    Number and type of AEs and/or UPs

  2. Phase II: Determine 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)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 66 Years   (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 and less than or equal to 66 years of age. Prior clinical trials have demonstrated safety for this conditioning regimen, cell therapy, and high-dose aldesleukin dose for patients up to 66 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. Concurrent systemic steroid therapy.
  6. History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine or aldesleukin.
  7. History of coronary revascularization or ischemic symptoms.
  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 60 years old
  9. 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

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): NCT02858310


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:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02858310     History of Changes
Other Study ID Numbers: 160154
16-C-0154
First Posted: August 8, 2016    Key Record Dates
Last Update Posted: August 31, 2018
Last Verified: August 27, 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) ):
Vulvar High Grade Squamous Intraepithelial Lesion
Vulvar Intraepithelial Neoplasia
Vaccine
Immunotherapy
Human Papillomavirus

Additional relevant MeSH terms:
Neoplasms
Cervical Intraepithelial Neoplasia
Vulvar Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Tumor Virus Infections
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Carcinoma in Situ
Papillomavirus Infections
Vulvar Diseases
Carcinoma
DNA Virus Infections
Virus Diseases
Genital Diseases, Female
Cyclophosphamide
Fludarabine
Aldesleukin
Interleukin-2
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-HIV Agents