A Phase I/II Clinical Trail of TC-E202 Targeting HPV16 E6 for Relapsed/Refractory to Standard Treatment or Metastatic Cervical Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Dose Limiting Toxicity or Maximum Tolerated Dose (MTD)
研究概览
简要总结
Background:
Cervical cancer is the most common gynecologic malignant tumor. The occurrence and progression of cervical carcinoma is firmly relevant to HPV (Human papilloma virus) infection. Cancer cells infected by HPV expressing an HPV protein called E6. E6 is the main factors of HPV 16 carcinogenesis. In TCR-T therapy, researchers take the blood of a certain patient, select T cells and insert genes into the cell that expressing a kind of protein that targeting HPV E6. The genetically engineered cells are called E6 TCR-T cells. The engineered cells are re-infused in the patients with cervical carcinoma.
Objective:
To evaluate the safety and efficacy of TCR-T cells in the treatment of cervical carcinoma.
Eligibility:
Adults aging 18-70 with relapsed/refractory to standard treatment or metastatic cervical carcinoma.
Design:
Patients will have many screening tests, including imaging procedures, heart and lung tests, and lab tests.
Patients 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.
Engineered T cells will be re-infused into the patients will stay in hospital and be evaluated.
详细描述
Background:
Cervical cancer is the most common gynecologic malignant tumor. The occurrence and progression of cervical carcinoma is firmly relevant to HPV (Human papilloma virus) infection.
Cancer cells infected by HPV expressing an HPV protein called E6. E6 is the main factors of HPV 16 carcinogenesis. T cells genetically engineered with a TCR targeting HPV-16 E6 (E6 TCR) display specific reactivity against HLA-A2+, HPV-16+ target cells.
T cell receptor (TCR) gene engineered T cells infusion can induce objective tumor responses in certain malignancies including HPV-16+ cancer.
Objective:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Be able to understand and sign the Informed of Consent Document. Be willing to follow the procedure and protocol of the clinical trial.
- •Age ≥ 18 years and ≤ 70 years.
- •Expected survival time > 3 months.
- •ECOG score 0-
- •Recurrent or metastatic cervical carcinoma based on TNM & FIGO staged histopathological investigation.
- •Received at least second-line standard treatment and diagnosed as PD through image assessment. (previously received radio-therapy, chemo-therapy, targeted-therapy or immune-therapy, wash-out period > 14 or 5 half life)
- •Be able provide fresh or preserved tissue specimen. (fresh specimen first, paraffine specimen or at least 12 tumor section, tumor tissue >20%)
- •At least 1 measurable lesion (according to RECIST1.1 standard）.
- •HPV16 positive.
- •HLA-A2 positive.
- •Hematology should at least meet the following criteria:
- •Absolute neutrophil count (ANC) ≥ 1.5× 109/L (±20%)； Platelet (PLT） ≥ 75× 109/L (±20%）； Hemoglobin (HGB) ≥ 90 g/L (±20%).
- •Blood biochemistry should at least meet the following criteria:
- •Serum creatinine (Cr) ≤ 1.5 times of upper limit of normal (ULN) or creatine clearance ≥ 60 ml/min; Serum Alanine aminotransferase (ALT) or/and Aspartate aminotransferase (AST) ≤ 2.5 times of upper limit of normal; Total bilirubin (TBIL) ≤ 15 times of upper limit of normal.
- •Blood coagulation function is normal: Prothrombin time (PT) ≤ 1.5 ULN, International Normalized Ratio (INR) ≤ 1.5 ULN, or Activated Partial Thromboplastin Time (APTT) ≤ 1.5 ULN.
- •Women of childbearing potential should be ascetic or take contraception since the signing of ICF to 24 weeks or later after the last administration of drug.
- •Recovered from toxic effect of previous treatment (CTCAE ≤ 1), or related AE(s) is not defined as safety issue.
- •Catheter insertion is feasible and No White Blood Cells collection contraindications.
排除标准
- •Under pregnancy or lactation, or positive based on blood pregnancy test.
- •Severe allergic to related ingredients in the clinical trial.
- •Received any other investigational treatment within 4 weeks before the first administration or enrolled in another clinical trial the same time (exception: the other treatment is observational and non-investigational or the patient is under follow-up period)
- •Primary central nerve system (CNS) cancer, or subjects with CNS metastasis after localized treatment (except patients without CNS metastasis, clinically stable and neither steroid treatment nor treatment for CNS metastasis).
- •Patients with active autoimmune disease or require systemic steroid treatment. (except patients with cutaneous condition but without systemic treatment, or subjects with asthma in childhood but without intervention after grown-up, or subjects with hypothyroidism mediated by autoimmune dysfunction and receiving thyroxine as replaced treatment)
- •Immunodeficiency including HIV positive, harvested or natural immunodeficiency.
- •Patients with ≥ grade 3 thromboembolic events within 2 years or under thrombolysis treatment.
- •Patients with hereditary or acquired hemorrhagic disease
- •Patients with cardiovascular disease or symptoms:
- •congestive heart failure (NYHA > 2); history of unstable angina pectoris; miocardial infarction within 48 weeks; clinically significant malignant arrhythmia (except atrial fibrillation and paroxysmal supraventricular tachycardia); Clinically significant prolonged QTcF (Male QTcF > 450 msec, Female QTcF > 470 msec); Uncontrolled hypertension.
- •Patients under active infection (except subjects with fever caused by tumor)
- •Patients with active tuberculosis, or history of active tuberculosis within 1 year before enrollment, or history of active tuberculosis over a year before enrollment but without standard treatment.
- •Patient with Active Hepatitis B or Active Hepatitis C.
- •Treponema pallidum antibody positive.
- •Received major surgery or under severe injury within 4 weeks before enrollment.
- •History of drug abuse, alcohol or drug addiction.
- •Received cell therapy before enrollment，such as TCR-T，CAR-T and TIL .
- •Allergic to IL-
- •Received treatment related chemo-therapy within 14 days of TC-E202 infusion (except lymphodepletion) .
- •Patient not suitable for the clinical trial according to investigators.
研究组 & 干预措施
TC-E202 dose
This study uses the "3+3" dose escalation method. The initial dose is Dose1, the maximum dose that patients can tolerate is determined as the phase II recommended dose (RPIID), and at least 6 patients are receiving RPIID treatment . If patients develop intolerance in Dose 1 (≥3 subjects with DLT), then the subsequent enrolled patients will receive Dose-1 infusion.
干预措施: TC-E202 cells (Biological)
TC-E202 dose
This study uses the "3+3" dose escalation method. The initial dose is Dose1, the maximum dose that patients can tolerate is determined as the phase II recommended dose (RPIID), and at least 6 patients are receiving RPIID treatment . If patients develop intolerance in Dose 1 (≥3 subjects with DLT), then the subsequent enrolled patients will receive Dose-1 infusion.
干预措施: IL-2 (Drug)
TC-E202 dose
This study uses the "3+3" dose escalation method. The initial dose is Dose1, the maximum dose that patients can tolerate is determined as the phase II recommended dose (RPIID), and at least 6 patients are receiving RPIID treatment . If patients develop intolerance in Dose 1 (≥3 subjects with DLT), then the subsequent enrolled patients will receive Dose-1 infusion.
干预措施: Fludarabine (Drug)
TC-E202 dose
This study uses the "3+3" dose escalation method. The initial dose is Dose1, the maximum dose that patients can tolerate is determined as the phase II recommended dose (RPIID), and at least 6 patients are receiving RPIID treatment . If patients develop intolerance in Dose 1 (≥3 subjects with DLT), then the subsequent enrolled patients will receive Dose-1 infusion.
干预措施: Cyclophosphamide Capsules (Drug)
结局指标
主要结局
Dose Limiting Toxicity or Maximum Tolerated Dose (MTD)
时间窗: Day 28 after the first TC-E202 infusion
Dose Limiting Toxicity (DLT) is defined as patients with the adverse event (AE) or laboratory abnormality recognized by SRC, and should be possibly related to TC-E202 cell therapy, and should be unrelated to the disease itself, disease progression, concomitant diseases or concomitant medication. 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.
Overall response rate
时间窗: Day0-Day730
The efficacy of TC-E202 will be assessed by the objective response rate (ORR) is evaluated according to RECIST 1.1 and iRECIST. ORR is described as patients assessed with partial response (PR) and complete response (CR).
Treatment-related adverse events as assessed by CTCAE v5.0
时间窗: Day0-Day730
The type, incidence and severity of adverse events include abnormal laboratory examination results with clinical significance after treatment, abnormal physical examination and blood examination results, bone marrow examination results, etc. Clinical and laboratory adverse events will be classified according to the National Cancer Institute general terminology standard for adverse events (NCI CTCAE) version 5.0.
次要结局
- Maximum Persistence (Cmax) of TC-E202(Day0-Day730)
- Time to Maximum Persistence(Day0-Day730)
- Area Under the Plasma Concentration-time Curve From Zero to Day 28 (AUC[0-28])(Day 28 after the first TC-E202 infusion)
- Anti-PD-1 single chain antibody concentration(Day0-Day730)
- Duration of response(Day0-Day730)
- Progression free survival(Day0-Day730)
- Overall survival(Day0-Day730)