T Cell Receptor Immunotherapy Targeting HPV-16 E6 for HPV-Associated Cancers

Study Overview
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Brief Summary
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Background: The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. Researchers want to test this on human papilloma virus (HPV)-associated cancers. Objective: - The purpose of this study is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (Anti-HPV E6) can shrink tumors associated with HPV and test the toxicity of this treatment. Eligibility: - Adults age 18-66 with an HPV-16-associated cancer. Design: Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti HPV E6 cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.} Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the anti HPV E6 cells and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment. Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits take up to 2 days.

Detailed Description
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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 E6 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. T cells genetically engineered with a TCR targeting HPV-16 E6 (E6 TCR) display specific reactivity against human leukocyte antigen serotype within HLA-A A serotype group (HLA-A2+), HPV-16+ target cells. OBJECTIVES: Primary Objective To determine a safe dose of administration of autologous T cells transduced with an anti-HPV-16 E6 TCR and aldesleukin to patients following a nonmyeloablative but lymphodepleting preparative regimen. To determine the objective tumor response rate (Complete or Partial Response) and duration in patients with metastatic or recurrent/refractory HPV-16+ cancers treated with this regimen. 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: Patients will receive a non-myeloablative lymphocyte-depleting preparative regimen of cyclophosphamide and fludarabine On day 0 patients will receive transduced lymphocytes and then begin high dose aldesleukin The study will begin with a phase I dose escalation. After the maximum tolerated dose (MTD) cell dose has been determined, the patients will be enrolled into the phase II portion of the study. Clinical and immunologic response will be evaluated about 4 to 6 weeks after treatment and then about every 1-6 months until disease progression Following a dose escalation phase of 9 to 18 patients, initially 21 evaluable patients will be enrolled in the phase II portion of the study. If 0 to 1 of the 21 patients experiences a clinical response, then no further patients will be enrolled. If 2 or more of the first 21 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled. The accrual ceiling will be set at 61 patients. Provided that about 1 patient every 6 weeks will be enrolled onto this trial, approximately 4 years may be needed to accrue the maximum number of patients.

Official Title
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A Phase I/II Study of T Cell Receptor Gene Therapy Targeting HPV-16 E6 for HPV-Associated Cancers

Conditions
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Vaginal Cancer, Cervical Cancer, Anal Cancer, Penile Cancer, Oropharyngeal Cancer

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Cyclophosphamide
* Biological: E6 TCR
* Drug: Aldesleukin


Participation Criteria
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Eligibility Criteria
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-INCLUSION CRITERIA Measurable metastatic or refractory/recurrent human papilloma virus (HPV-16+) cancer (determined by in situ hybridization (ISH) or a polymerase chain reaction (PCR)-based test). Patients must be human leukocyte antigens (HLA-A) 02:01-positive. All patients must have received prior first line standard therapy or declined standard therapy, and have been either non-responders (progressive disease) or have recurred. Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible. Greater than or equal to 18 years of age and less than or equal to 70 years of age. Able to understand and sign the Informed Consent Document. Willing to sign durable power of attorney Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1. Life expectancy of greater than 3 months. Patients of both genders must be willing to practice birth control from the time of enrollment on this study up to 4 months after treatment. Patients must be willing to undergo testing for HPV-16 prior to becoming pregnant. Women of child bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus. Serology: 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 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 reverse transcription polymerase chain reaction (RT-PCR) and be hepatitis C virus ribonucleic acid (HCV RNA) negative. Hematology: Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim. White blood cell (WBC) greater than or equal to 3000/mm^3 Platelet count greater than or equal 100,000/mm^3 Hemoglobin greater than 8.0 g/dL Chemistry: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than or equal to 2.5 times the upper limit of normal Serum creatinine less than or equal to 1.6 mg/dL Total bilirubin less than or equal to to 1.5 mg/dL, except in patients with Gilberts Syndrome who must have a total bilirubin less than 3.0 mg/dL More than 4 weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen. EXCLUSION CRITERIA: Women of childbearing potential who are pregnant or breastfeeding. There are potentially dangerous side effects of the treatment on the fetus or infant. 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, obstructive or restrictive pulmonary disease. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease). 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). Concurrent systemic steroid therapy. History of severe immediate hypersensitivity reaction to cyclophosphamide or fludarabine. History of coronary revascularization or ischemic symptoms. Documented left ventricular ejection fraction (LVEF) of less than or equal to 45% tested. The following patients will undergo cardiac evaluations a. clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or b. age greater than or equal 60 years old

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T Cell Receptor Immunotherapy<br>patients will receive cyclophosphamide and fludarabine followed by infusion of the human papilloma virus (HPV) E6 T cell receptor (TCR), followed by high dose aldesleukin | Drug: Fludarabine<br>* Patients will receive Fludarabine 25 mg/m^2/day for 5 days.<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* Patients will receive Cyclophosphamide 60 mg/kg/day x 2 days<br>* Other names: Cytoxan;Biological: E6 TCR<br>* On day 0, cells will be infused intravenously (IV) over 20-30 minute (between 1 and 4 days after the last dose of fludarabine)<br>Drug: Aldesleukin<br>* Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).<br>* Other names: IL-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | The MTD is the highest dose at which ≤1 of 6 patients experienced a dose limiting toxicity (DLT) or the highest dose level studied if DLTs are not observed at any of the dose levels. | participants were followed for the duration of hospital stay, an average of 3 weeks | 
| Objective Tumor Response Rate (Complete or Partial Response) | Objective tumor response rate is defined as the number of participants with a complete or partial response per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. | 4 years | 
| Duration of Response | Duration of response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progression is at least a 20% increase in the sum of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | up to one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious and Non-serious Adverse Events | Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0). 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. | 19 months and 7 days | 
| Number of Participants With a Dose Limiting Toxicity (DLT) | A dose limiting toxicity is all Grade 3 and greater toxicities with the exception of myelosuppression, defined as lymphopenia, neutropenia, decreased hemoglobin, and thrombocytopenia, due to chemotherapy preparative regimen. Aldesleukin expected toxicities as defined in Appendix 2 and 3 of the protocol. Expected chemotherapy toxicities as defined in the pharmaceutical information section. Immediate hypersensitivity reactions (excluding symptomatic bronchospasm and grade 4 hypotension) occurring within 2 hours of cell infusion (related to cell infusion) that are reversible to a grade 2 or less within 24 hours of cell administration with standard therapy. Grade 3 fever. Events that are clearly related to the patient's disease. | 19 months and 7 days | 
| Percentage of Cluster of Differentiation 3 (CD3+) Cells That Are E6 T-Cell Receptor Memory of Circulating T-Cells in Responders and Non-responders | Detection of E6 TCR T cells in patients peripheral blood leukocytes (PBL)/apheresis samples by flow cytometry. | One month after treatment | 
| Expression of Programmed Cell Death 1 (PD-1) by Circulating E6 T-Cell Receptor (TCR) T-Cells | Presence of PD-1 on circulating lymphocytes by flow cytometry one month after treatment. | one month after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diet, Screening, HPV positive, Metastatic, Risk Factors, Colorectal adenoma, Refractory, Immunotherapy, Reproductive Cancers