Background: Human papillomavirus (HPV) can cause cervical, throat, anal, and genital cancers. Cancers caused by HPV have an 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 T cell receptor (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.
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 human leukocyte antigen (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 Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
224
T cells genetically engineered with a T cell receptor (TCR) targeting human papillomavirus (HPV -16 E7 (E7 TCR) that display specific reactivity against human leukocyte antigen (HLA-A2+, HPV-16+ target cells.
Following cell infusion, the patient receives high-dose bolus aldesleukin, which is dosed to individual patient tolerance. Aldesleukin improves the survival of E7 T cell receptor (TCR) cells after infusion.
Part of the non-myeloablative lymphocyte-depleting preparative regimen.
Part of the non-myeloablative lymphocyte-depleting preparative regimen.
Screening/Baseline. Follow-up (end of treatment).
Screening/Baseline. Following treatment (6 weeks post treatment preferred) and at disease progression only.
Screening/Baseline. Follow-up (end of treatment). 40 days (+/- 2 weeks) after cell infusion; additional visits as indicated.
Screening/Baseline.
Supportive medication for nausea/vomiting/anorexia. 0.01 mg/kg intravenous (IV) every(q) day as needed (prn).
Supportive medication for nausea/vomiting/anorexia. Ondansetron 10mg intravenous (IV) every(q) 8 hours(hr) as needed (prn).
Supportive medication for nausea/vomiting/anorexia. 1mg intravenous (IV) at 4-6 hours(h) as needed (prn).
Supportive medication for nausea/vomiting/anorexia. 25mg per rectum (PR) as needed (prn) or 10mg intravenous (IV) every(q) 6hours(h) prn.
Supportive medication for diarrhea. 2.5mg by mouth (po) every(q) 3 hours(h) as needed (prn).
Supportive medication for diarrhea. 25mcg by mouth (po) every(q) 3 hours(h) as needed (prn).
Supportive medication for diarrhea. 30-60mg by mouth (po) every(q) 4 hours(h) as needed (prn).
Supportive medication for diarrhea. 2mg by mouth (po) every(q) 3 hours(h) as needed (prn).
Supportive medication for fever. 50-75mg by mouth (po) every(q) 8 hours(h).
Supportive medication for fever. 650mg by mouth (po) every 4 hours (q) 4hr.
Supportive medication for pruritis. 25-50mg by mouth (po) every 4 hours (q) 4hr as needed (prn).
Supportive medication for pruritis. 10-20mg by mouth (po) every 6 hours(h), as needed (prn).
Supportive medication for chills. 25-50mg intravenous (IV) every 1 hour (q1hr), as needed (prn).
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States
Phase II: Overall Response Rate Partial Response + Complete Response (PR +CR)
Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Compete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
Time frame: At 12 weeks, every 3 months x 3, and every 6 months for approximately 5 years
Phase I: Number of Dose Limiting Toxicities (DLT)
Adverse events were assessed by the Common Terminology Criteria for Adverse Events v4.0. Grade 3 is serious. Grade 4 is life-threatening. Grade 5 is death related to adverse event. A DLT is defined as all Grade 3 and greater toxicities occurring within 30 days of the cell infusion with the exception of: Cytokine Release Syndrome (CRS) that resolves ≤ grade 2 within 14 days of the last dose of aldesleukin. Autoimmune toxicity that resolves to ≤ grade 2 within 14 days for starting symptom treatment (e.g. steroids). Cardiac, gastrointestinal, dermatological, hepatic, pulmonary, renal, hematologic, neurologic toxicity, or toxicity in Appendix C of the protocol attributable to aldesleukin that resolves to ≤ grade 2 within 14 days of the last dose of aldesleukin. Transient grade 3 hypoxia associated with cell infusion that corrects to ≤ grade 2 with supplemental oxygen and/or that resolves to ≤ grade 2 within 24 hours or before starting aldesleukin.
Time frame: From the day of cell infusion (Day 0) to Day +30
Progression-free Survival
Progression-free survival is the time from start of treatment to disease progression or death from any cause. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Disease progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.
Time frame: From the time of cell infusion (Day 0) until documented progressive disease; a maximum of 12 months
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