EPITOME-1015-I: a Phase I Study to Investigate the Safety, Tolerability and Preliminary Efficacy of a Third Generation TCR-T Therapy, MDG1015, in Epithelial Ovarian Carcinoma, Gastroesophageal (Junction) Adenocarcinoma, Myxoid (Round Cell) Liposarcoma And/or Synovial Sarcoma Subjects with Advanced Disease Expressing NY-ESO-1 And/or LAGE-1a
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- Medigene AG
- 入组人数
- 55
- 试验地点
- 1
- 主要终点
- DE Segment: Adverse Events and Dose Limiting Toxicities (Safety and Tolerability)
研究概览
简要总结
MDG1015 is a third generation TCR-T therapy product targeting NY-ESO-1/LAGE-1a armored and enhanced by the PD1-41BB costimulatory switch protein (CSP). The study purpose is to establish the safety, tolerability and preliminary efficacy of MDG1015 in patients with epithelial ovarian cancer, gastroesophageal adenocarcinoma, round cell liposarcoma and/or synovial sarcoma that expresses NY-ESO-1 and/or LAGE-1a.
The main questions this clinical trial aims to answer are:
Can this TCR-T therapy MDG1015 be given to patients safely? What is the optimal dose of the TCR-T therapy MDG1015? If and what side effects do participants experience after receiving the TCR-T therapy MDG1015? Do participants experience a potential disease response after receiving the TCR-T therapy MDG1015?
Participants will:
Receive (in most cases) 1 single infusion of MDG1015 at a pre-defined dose level and will be followed up regularly up to 1 year. After one year, participants will enter the long term follow-up part up to 15 years after being treated. Any side effects and/or potential disease response will be documented during this period.
详细描述
The clinical study consists of screening, leukapheresis of mononuclear cells, LDC, followed by a single MDG1015 infusion on Day 0 and a subsequent hospitalization period of at least 3 days for in-patient safety monitoring. All Subjects who have received an MDG1015 infusion will continue to be followed regularly for safety and efficacy assessments in a post-treatment follow-up through month 12 (Y1) and long-term follow-up (LTFU) through years 2 - 15 in an out-patient setting. Dose Escalation Segment (DE) will evaluate an anticipated number of 4 dose levels to establish the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). During the cohort expansion (CE) segment the MTD/RP2D will be confirmed
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult, ≥ 18 years of age and weigh ≥ 40 kg for Dose levels 1-3 and ≥ 50 kg for Dose level 4
- •Subject must have a confirmed diagnosis of either High grade serous or endometrioid ovarian, primary peritoneal or fallopian tube cancer Gastric or esophageal (junction) adenocarcinoma Myxoid (round cell) liposarcoma Synovial sarcoma
- •Subject's must have tested positive for HLA-A*02:01 genotype by a Sponsor designated central laboratory
- •Subject's tumor must have tested positive for NY-ESO-1 and/or LAGE-1a mRNA expression by a Sponsor designated central laboratory Both ≤1 year old archival tissue or fresh biopsy are allowed
- •Subjects diagnosed with an eligible indication must have exhausted treatment options with proven survival benefit
- •Subjects must have
- •measurable disease
- •Life expectancy ≥ 3 months per Investigator's opinion
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- •Adequate vital organ function
- •Adequate bone marrow function
- •Adequate coagulation profile
- •Toxicities from prior/ongoing therapies must have recovered to ≤ Grade 2 according to the CTCAE v5.0 or Subject's baseline excluding alopecia
- •Prior toxicities related to surgical procedures should have recovered to Grade ≤ 1
- •Women of childbearing potential (WCBP) or men who can father children must be willing and able to use adequate (e.g. barrier or licensed hormonal methods)
排除标准
- •Any uncontrolled medical or psychiatric disorder that would preclude participation as outlined
- •HLA-A*02:02 or HLA-A*02:03 genotype
- •Pregnant or lactating women
- •Viral serology:
- •Known infection with HIV-1/2, CMV (CMV required only for U.S. sites) or HTLV-1/2,
- •Active infection with HBV or HCV
- •Positive test for Mycoplasma or Treponema Pallidum
- •Uncontrolled infection(s) requiring intravenous anti-bacterial, anti-viral or anti-fungal treatment within 14 days prior to the first dose of LDC (patients receiving prophylactic antibiotics are eligible)
- •Inadequate venous access for or contraindications to leukapheresis
- •Contraindications or life-threatening allergies, hypersensitivity, or intolerance to MDG1015 excipients, LDC agents, rasburicase, methylprednisolone or tocilizumab.
- •Untreated CNS metastases or active CNS metastases (progressing or requiring corticosteroids for symptoms control) and leptomeningeal disease
- •Unstable/active ulcer, varices, or digestive tract bleeding or recent digestive surgery that may have increased risk of bleeding
- •History of another primary malignancy that requires intervention beyond surveillance or that has not been in remission for at least 1 year. The following are exempt from the 1-year limit:
- •non-melanoma skin cancer
- •curatively treated localized prostate cancer
- •carcinoma in situ (e.g. cervix, bladder, breast)
- •NYHA Class ≥ II, heart failure, unstable angina, a history of recent (≤ 6 months) arrythmias, myocardial infarction or sustained (> 30 seconds) ventricular tachyarrhythmias
- •Subjects who are dependent on dialysis
- •Subjects with a history of pulmonary embolism or deep vein thrombosis that cannot safely withhold anti-coagulant therapy from leukapheresis until 7 days after administration of MDG1015 as determined by the Investigator
- •Active autoimmune disease requiring systemic therapy except for adequately controlled Type 1 diabetes mellitus, autoimmune hypothyroidism or Grave's disease
- •Previous allogeneic hematopoietic stem cell transplant within the last 5 years or solid organ transplant
- •Specific to GAC/GEJ Subjects:
- •Positive history of esophageal or gastric resection that the Investigator considers is at increased risk of bleeding or perforation
研究组 & 干预措施
Administration of MDG1015
MDG1015 is a first-in-class, 3rd generation TCR-T therapy consisting of autologous, patient-derived CD8+ T cells that are transduced with a New York esophageal squamous cell carcinoma-1 (NY-ESO-1)/ L antigen family member-1a (LAGE-1a)-specific, human leukocyte antigen (HLA)-A*02:01-restricted T cell receptor (TCR) and the costimulatory switch protein (CSP) programmed cell death protein 1 (PD1)-41BB administered following lymphodepletion chemotherapy.
干预措施: Lymphodepletion (Drug)
Administration of MDG1015
MDG1015 is a first-in-class, 3rd generation TCR-T therapy consisting of autologous, patient-derived CD8+ T cells that are transduced with a New York esophageal squamous cell carcinoma-1 (NY-ESO-1)/ L antigen family member-1a (LAGE-1a)-specific, human leukocyte antigen (HLA)-A*02:01-restricted T cell receptor (TCR) and the costimulatory switch protein (CSP) programmed cell death protein 1 (PD1)-41BB administered following lymphodepletion chemotherapy.
干预措施: TCR-T cells (MDG1015) (Biological)
结局指标
主要结局
DE Segment: Adverse Events and Dose Limiting Toxicities (Safety and Tolerability)
时间窗: 28 days
Incidence and severity of adverse events to establish RP2D measured by dose limiting toxicities (DLTs) up to 28 days post infusion
Exp Segment: Adverse Events (Safety)
时间窗: 12 months
Incidence of (S)AEs by type, grade and duration
次要结局
- Objective response rate (ORR)(12 months)
- Assess feasibility of MDG1015 generation in study population(2 years)
- Correlation of blood levels and the onset and/or severity of IP-related toxicities(12 months)
- Clinical benefit rate (CBR)(12 months)
- Duration of response (DOR)(12 months)
- Overall survival (OS)(15 years)
- Progression Free Survival (PFS)(12 months)
- Best overall response (BOR)(12 months)
- Time to response (TTR)(12 months)
- Levels of MDG1015 in blood over time(12 months)