A Phase I/II Trial of T Cell Receptor Gene Therapy Targeting HPV-16 E7 for HPV-Associated Cancers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 224
- 试验地点
- 2
- 主要终点
- Phase II: Overall Response Rate Partial Response + Complete Response (PR +CR)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 120 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •Measurable metastatic or refractory/recurrent human papillomavirus (HPV-16+ cancer (determined by in situ hybridization (ISH) or a polymerase chain reaction (PCR)-based test).
- •Patients must be human leukocyte antigen (HLA-A*02 by low resolution typing, and HLA-A*02:01 by one of the high-resolution type results.
- •All patients must have received prior first line standard therapy or declined standard therapy.
- •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.
- •Greater than or equal to 18 years of age.
- •Able to understand and sign the Informed Consent Document.
- •Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or
- •Individuals must be willing to practice birth control from the time of enrollment on this study up to twelve (12) months after treatment. Individuals must be willing to undergo testing for HPV-16 prior to becoming pregnant after this period.
- •Individuals of childbearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus. Individuals of childbearing potential are defined as all individuals except individuals who are postmenopausal or who have had a hysterectomy. Postmenopausal will be defined as individuals 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 infant's secondary to treatment of the mother with E7 T cell receptor (TCR) transduced peripheral blood lymphocytes (PBLs), breastfeeding should be discontinued if the individual is treated with E7 TCR transduced PBL. These potential risks may also apply to other agents used in this study.
- •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 (HCV) ribonucleic acid (RNA) negative.
- •a. Hematology:
- •Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim.
- •White blood count (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 Alanine aminotransferase (ALT)/Aspartate aminotransferase (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.
排除标准
- •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.
- •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).
- •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.
- •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;
- •Steroids as premedication for hypersensitivity reactions (e.g., computed tomography (CT) scan premedication)
- •History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine or aldesleukin.
- •Patients with a history of coronary revascularization or ischemic symptoms unless patient has a normal cardiac stress test.
- •Documented left ventricular ejection fraction (LVEF) of less than or equal to 45% tested. The following patients will undergo cardiac evaluations
- •Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or
- •Age greater than or equal to 50 years old
- •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.
- •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
研究组 & 干预措施
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: E7 TCR cells (Biological)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Aldesleukin (Drug)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Fludarabine (Drug)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Cyclophosphamide (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: E7 TCR cells (Biological)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Aldesleukin (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Fludarabine (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Cyclophosphamide (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Acetaminophen (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Indomethacin (Drug)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: EKG (Diagnostic Test)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Biopsy (Procedure)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Chest CT and MRI or PET (Diagnostic Test)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: PFT (Diagnostic Test)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Granisetron (Drug)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Ondansetron (Drug)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Droperidol (Drug)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Prochlorperazine (Drug)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Diphenoxylate HCL (Drug)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Atropine sulfate (Drug)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Codeine sulfate (Drug)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Loperamide (Drug)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Indomethacin (Drug)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Acetaminophen (Drug)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Diphenhydramine HCL (Drug)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Hydroxyzine HCL (Drug)
Arm 1: Phase I
Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 T cell receptor (TCR) Cells at escalating doses, followed by aldesleukin.
干预措施: Meperidine (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: EKG (Diagnostic Test)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Biopsy (Procedure)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Chest CT and MRI or PET (Diagnostic Test)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: PFT (Diagnostic Test)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Granisetron (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Ondansetron (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Droperidol (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Prochlorperazine (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Diphenoxylate HCL (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Atropine sulfate (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Codeine sulfate (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Loperamide (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Diphenhydramine HCL (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Hydroxyzine HCL (Drug)
Arm 2: Phase II
1 x 10^e11 E7 Cells that was determined in Phase I + aldesleukin.
干预措施: Meperidine (Drug)
结局指标
主要结局
Phase II: Overall Response Rate Partial Response + Complete Response (PR +CR)
时间窗: At 12 weeks, every 3 months x 3, and every 6 months for approximately 5 years
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.
Phase I: Number of Dose Limiting Toxicities (DLT)
时间窗: From the day of cell infusion (Day 0) to Day +30
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.
次要结局
- Progression-free Survival(From the time of cell infusion (Day 0) until documented progressive disease; a maximum of 12 months)
研究者
Scott Norberg, D.O.
Principal Investigator
National Cancer Institute (NCI)