Clinical Trials /

E7 TCR T Cells for Human Papillomavirus-Associated Cancers

NCT02858310

Description:

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 18-70 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.

Related Conditions:
  • Anal Carcinoma
  • Cervical Carcinoma
  • Oropharyngeal Carcinoma
  • Penile Carcinoma
  • Vaginal Carcinoma
  • Vulvar Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: E7 TCR T Cells for Human Papillomavirus-Associated Cancers
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 160154
  • SECONDARY ID: 16-C-0154
  • NCT ID: NCT02858310

Conditions

  • Papillomavirus Infections
  • Cervical Intraepithelial Neoplasia
  • Carcinoma In Situ
  • Vulvar Neoplasms
  • Vulvar Diseases

Interventions

DrugSynonymsArms
E7 TCR cellsArm 1: Phase I
AldesleukinArm 1: Phase I
FludarabineArm 1: Phase I
CyclophosphamideArm 1: Phase I

Purpose

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 18-70 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.

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 70 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1: Phase IExperimentalNon-myeloablative, lymphocyte depleting preparative regimen, followed by E7 TCR Cells at escalating doses, followed by aldesleukin.
  • E7 TCR cells
  • Aldesleukin
  • Fludarabine
  • Cyclophosphamide
Arm 2: Phase IIExperimental1 x 10 e11 E7 Cells that was determined in Phase I +aldesleukin
  • E7 TCR cells
  • Aldesleukin
  • Fludarabine
  • Cyclophosphamide

Eligibility 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 70 years of
                  age.

                  Note: This age range is consistent with the age of patients with the disease
                  being studied.

               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. 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. 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
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: Determine a safe dose for E7 TCR cells plus aldesleukin
Time Frame:30 days after treatment
Safety Issue:
Description:Number and type of AEs and/or UPs

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Vulvar High Grade Squamous Intraepithelial Lesion
  • Vulvar Intraepithelial Neoplasia
  • Vaccine
  • Immunotherapy
  • Human Papillomavirus

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