A Phase 1/2, First-in-Human, Open-Label, Accelerated-Titration, Two-Part Clinical Trial of TK-8001 (MAGE-A1-Directed TCR-Transduced Autologous CD8+ T-cells) in Patients With HLA-A*02:01 Genotype and Advanced-Stage/Metastatic, MAGE-A1+ Solid Tumors That Either Have No Further Approved Therapeutic Alternative(s) or Are Not Eligible for Them or Are in a Non- Curable State and Have Received a Minimum of Two Lines of Systemic Therapy
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- T-knife GmbH
- 入组人数
- 23
- 试验地点
- 28
- 主要终点
- Preliminary anti tumor activity
研究概览
简要总结
The aim of this study is to determine the safety, tolerability and anti-tumoral activity of autologous T cells transduced with a T cell receptor specific for MAGE-A1 in eligible patients with advanced solid tumors.
详细描述
This is a Phase 1/2, first-in-human, open-label, accelerated titration, two-part clinical trial of TK-8001 (MAGE-A1-directed TCR-transduced autologous CD8+ T-cells) in subjects with HLA-A*02:01 genotype and advanced stage/metastatic, MAGE-A1+ solid tumors (including but not limited to melanoma [skin or uveal], NSCLC, urothelial, breast, gastric [including gastroesophageal junction], esophageal, sarcoma, HNSCC, HCC, biliary tract, cervical, and salivary gland cancer) that either have no further approved therapeutic alternative or are not eligible for them or that are in a non-curable state as per the Investigator's assessment and have received a minimum of two lines of systemic therapy.
This two-part clinical trial will consist of a Phase 1 Part, which includes dose-escalation and expansion, and a Phase 2 Part.
In the Phase 1 Part dose-escalation, at least 6 subjects and up to 18 subjects (if DLT occurs) will receive escalating doses of TK-8001, with up to three dose levels explored. During the Phase 1 Part expansion, up to 20 additional subjects may be treated on DL3 if cleared during dose escalation to further evaluate the safety and efficacy of TK-8001 (Cohort 1).
An additional cohort of up to 10 subjects with brain metastases (Cohort 2) may also be treated on DL3 if cleared during dose-escalation. The maximum total number of subjects to be treated on DL3 during Phase 1 will be 33 subjects.
In the Phase 2 Part, up to 30 patients will receive TK-8001 to further evaluate the efficacy and safety of TK-8001 and to confirm the RP2D.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able to understand and comply with study procedures
- •At least 18 years old
- •Phase 1 Part dose-escalation and Phase 1 Part expansion Cohort 1 only: Presence of an advanced-stage/metastatic, solid tumor in non-curable state as per current medical knowledge, for which there is either no further approved therapeutic alternative available or the subject is not eligible for them or, for which the subject has completed a minimum of two lines of approved systemic therapy in the advanced-stage/metastatic setting.
- •Phase 1 Part expansion Cohort 2 only: Presence of an advanced-stage/metastatic disease of the following indications: melanoma (skin or uveal), NSCLC, urothelial, breast cancer in non-curable state as per current medical knowledge, for which there is either no further approved therapeutic alternative available or the subject is not eligible for them or, for which the subject has completed a minimum of two lines of approved systemic therapy in the advanced-stage/metastatic setting.
- •HLA-A*02:01 genotype.
- •MAGE-A1+ tumor positive for MAGE-A1
- •At least one measurable lesion, that can be accurately measured as per RECIST Version 1.1
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
- •Life expectancy > 3 months as assessed by the Investigator
- •All toxicities related to prior therapy must have recovered to baseline or Grade ≤ 1 based on CTCAE v5.0
- •Immune-related adverse events (irAEs) from previous therapies must have recovered to baseline or Grade ≤ 1
排除标准
- •Any tumor-directed therapy within 14 days before start of conditioning therapy
- •Any other MAGE-A1-targeting therapy.
- •Pre-existing arrhythmia, uncontrolled angina pectoris, presently uncontrolled heart failure, or any myocardial infarction/coronary event as well as any thromboembolic event at any time < 6 months prior to screening.
- •Left ventricular ejection fraction (LVEF) < 45% as measured by an echocardiogram
- •History of CNS disease such as stroke, seizure, encephalitis, or multiple sclerosis (within 6 months prior to screening)
- •Active allergy requiring continuous systemic medication or active infections requiring IV/PO anti-infectious therapy
- •History of or clinical evidence of CNS primary tumors or metastases, unless they have been previously treated, and have been stable for at least 4 weeks prior to trial entry
- •Major surgery within last 4 weeks prior to consent
- •Active disease/ongoing infection with HIV, HBV, HCV, TB, syphilis, or SARS-CoV-2
- •Receipt of any organ transplantation, except for transplants that do not require immunosuppression
- •Any vaccine administration within 4 weeks of IP administration.
结局指标
主要结局
Preliminary anti tumor activity
时间窗: Up to 15 years after TK-8001 treatment, or until disease progression
Evaluation of overall response rate (ORR), stable disease rate (SD), partial response rate (PR), and complete response (CR) rate of TK-8001 monotherapy, according to RECIST Version 1.1 and modified Response Evaluation Criteria in Solid Tumors (RECIST, V1.1) in cancer immunotherapy trials (iRECIST)
Safety and tolerability
时间窗: Up to 15 years after TK-8001 treatment (1 year short-term follow-up, 14 years long-term follow up)
Incidence and grade of treatment-emergent adverse events (AEs) and serious adverse events (SAEs); Number and type of dose limiting toxicities (DLT)
次要结局
- End of dose escalation(28 days after TK-8001 treatment of last patient in Phase 1)