Multicenter, Open-label, Adaptive Design Phase I Trial With Genetically Modified T-cells Carrying Universal Chimeric Antigen Receptors (UniCAR02-T) in Combination With CD123 Target Module (TM123) for the Treatment of Patients With Hematologic and Lymphatic Malignancies Positive for CD123
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 32
- 试验地点
- 10
- 主要终点
- Safety and tolerability
研究概览
简要总结
This dose-escalating phase I trial assesses for the first time the safety, the side effects and the harmlessness, as well as the therapeutical benefit of the new study drug UniCAR02-T-CD123 in patients with hematologic and lymphatic malignancies positive for CD123 marker. The UniCAR02-T-CD123 drug is a combination of a cellular component (UniCAR02-T) with a recombinant antibody derivative (TM123) which together forms the active drug.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
In the expansion cohort 2 different TM123 dose levels shall be compared descriptively.
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
- •Phase 1a Dose Escalation:
- •Inclusion Criteria:
- •Male or female patients, age ≥ 18 years
- •Documented definitive diagnosis of Relapsed or refractory AML (according to standard of care testing) and CD123 positivity of ≥20 % of blasts. MRD+ AML without morphological relapse or refractoriness may be included with the sponsor's approval
- •Eastern Cooperative Oncology Group (ECOG) of 0 to 1
- •Life expectancy of at least 2 months
- •Adequate renal and hepatic laboratory assessments
- •Adequate cardiac function
- •Long-term venous access existing (e.g. port-system) resp. acceptance of implantation of a device
- •Able to give written informed consent
- •Weight ≥ 45 kg
- •Negative pregnancy test; routinely using a highly effective method of birth control
排除标准
- •Acute promyelocytic leukemia
- •AML with only extramedullary manifestations (e.g., chloroma, primary myeloid sarcoma).
- •Refractory disease under anti-leukemic treatment lasting longer than 6 months
- •Current manifestation of AML in central nervous system
- •Bone marrow failure syndromes (e.g. Fanconi anemia, Kostman syndrome, Shwachman syndrome)
- •Significant cardiac disease: i.e., heart failure (NYHA III or IV); unstable coronary artery disease, myocardial infarction or serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy within the last 12 months prior to study entry that may in the Investigator's opinion interfere with participation in the trial.
- •Patients undergoing renal dialysis
- •Pulmonary disease with clinically relevant hypoxia
- •Parkinson's disease, epilepsy, stroke, seizures, significant paresis or aphasia with clinical symptoms in the previous 12 months that may in the Investigator's opinion interfere with participation in the trial.
- •Disseminated intravascular coagulation (DIC) within 3 months prior to the planned start of the study treatment.
- •Hemorrhagic cystitis
- •Active infectious disease considered by investigator to be incompatible with protocol or being contraindications for lymphodepletion therapy
- •Allogeneic stem cell transplantation within last two months or GvHD requiring systemic immunosuppressive therapy
- •Vaccination with live viruses within 2 weeks prior to lymphodepletion therapy
- •Major surgery within 28 days (prior to start of TM123 infusion)
- •Other malignancy requiring active therapy, but adjuvant endocrine therapy is allowed
- •Treatment with any investigational drug substance or experimental therapy within 4 weeks or 5 half-lives (whatever is shorter) of the substance prior to the day of apheresis
- •Prior treatment with gene therapy products unless approved by the sponsor
- •Use of checkpoint inhibitors within 5 half-lives of the respective substance
- •Pregnant or breastfeeding women
- •Currently significant psychologic disorder, including substance abuse
- •Known history of human immunodeficiency virus (HIV) or human T-lymphotropic virus (HTLV) or active/chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)
- •Any significant autoimmune disease requiring systemic immunosuppressive therapy or that may otherwise, in the Investigator's opinion, interfere with participation in the trial, or documented presence of autoantibodies against La/SS-B.
- •Phase 1b Dose Expansion:
- •Inclusion Criteria:
- •Male or female patients, age ≥ 18 years
- •Relapsed or refractory AML (according to standard of care testing), having up to 30% blasts in a bone marrow assessment at either screening or prescreening, or patients having between 30% and 40% blasts for 2 consecutive bone marrow assessments with a minimum of 1 months and no more than 2 months apart, and without hyperproliferative disease requiring cytoreductive treatment, up to 3rd relapse, without further approved curative or life-extending treatment options, and documented CD123 positivity of ≥ 20 % of blasts. Exceptions to BM blast criterion are only possible in minor deviations in timing and/or blast count in clinically stable patients, and only with written sponsor approval. Exemptions to CD123 expression are not allowed. MRD+ AML without morphological relapse or refractoriness may be included with the sponsor's approval.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- •Life expectancy of at least 2 months
- •Adequate renal and hepatic laboratory assessments:
- •Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) ≤ 2.5× upper limit of normal (ULN)
- •Total bilirubin ≤ 1.5× ULN
- •Serum creatinine clearance at least 70 mL/min)
- •Adequate cardiac function, i.e., left ventricular ejection fraction (LVEF) of ≥ 50 %.
- •Long-term venous acces existing (e.g., port-system) resp. acceptance of implantation of a device
- •Able to give written informed consent
- •Weight ≥ 45kg
- •Negative pregnancy test; routinely using a highly effective method of birth control
- •Exclusion criteria:
- •Acute promyelocytic leukemia (t15;17)
- •AML with only extramedullary manifestations (e.g., chloroma, primary myeloid sarcoma)
- •Refractory disease under anti-leukemic treatment lasting longer than 6 months
- •Current manifestion of AML in central nervous system
- •Bone marrow failure syndromes (e.g. Fanconi anemia, Kostman syndrome, Schwachman syndrome)
- •Significant cardiac disease: i.e., heart failure (NYHA III or IV); unstable coronary artery disease, myocardial infarction or serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy within the last 12 months prior to study entry that may in the Investigator''s opinion interfere with participation in the trial.
- •Patients undergoing renal dialysis
- •Pulmonary disease with clinically relevant hypoxia
- •Parkinson's disease, epilepsy, stroke, seizures, significant paresis or aphasia with clinical symptoms in the previous 12 months that may in the Investigator's opinion interfere with participation in the trial.
- •Disseminated intravascular coagulation (DIC) within 3 months prior to the planned start of the study treatment.
- •Hemorrhagic cystitis
- 另有 12 项未显示
研究组 & 干预措施
UniCAR02-T-CD123 (4 mg/day TM123)
Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 4 mg/day of the recombinant antibody derivative TM123.
干预措施: Cyclophosphamide (Non-IMP) (Drug)
UniCAR02-T-CD123 (4 mg/day TM123)
Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 4 mg/day of the recombinant antibody derivative TM123.
干预措施: Fludarabine (Non-IMP) (Drug)
UniCAR02-T-CD123 (4 mg/day TM123)
Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 4 mg/day of the recombinant antibody derivative TM123.
干预措施: TM123 (IMP) (Drug)
UniCAR02-T-CD123 (4 mg/day TM123)
Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 4 mg/day of the recombinant antibody derivative TM123.
干预措施: UniCAR02-T (IMP) (Drug)
UniCAR02-T-CD123 (8 mg/day TM123)
Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 8 mg/day of the recombinant antibody derivative TM123.
干预措施: Cyclophosphamide (Non-IMP) (Drug)
UniCAR02-T-CD123 (8 mg/day TM123)
Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 8 mg/day of the recombinant antibody derivative TM123.
干预措施: Fludarabine (Non-IMP) (Drug)
UniCAR02-T-CD123 (8 mg/day TM123)
Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 8 mg/day of the recombinant antibody derivative TM123.
干预措施: TM123 (IMP) (Drug)
UniCAR02-T-CD123 (8 mg/day TM123)
Preconditioning (lymphodepletion) with cyclophosphamide and fludarabine, followed by combination treatment of genetically modified T-cells carrying universal chimeric antigen receptors (UniCAR02-T) with 8 mg/day of the recombinant antibody derivative TM123.
干预措施: UniCAR02-T (IMP) (Drug)
结局指标
主要结局
Safety and tolerability
时间窗: Infusion period of TM123 (up to 20 days) + 7 days resp. 14 days in patients with complete blast clearance during the IC or until Safety Follow-up 1 (infusion period of TM123 + 28 days + 3 months)
Incidence and intensity of adverse events graded according to CTCAE V5.0 with the exception of CRS and ICANS graded according to Lee et al. 2014 and Lee et al. 2019 respectively
Recommended phase 2 dose (RP2D)
时间窗: Infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance)
Establishing recommended phase 2 dose (RP2D) and schedule
Response
时间窗: Infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance)
Complete remission (CR, CRh, CRi, CRMRDneg, CRMRDpos) and partial remission (PR) at any time point and duration of responses
次要结局
- Best response rate(until fifteen years after last UniCAR02-T administration)
- Establishing recommended phase 2 dose (RP2D)(DLT period (infusion period of TM123 (up to 20 days) + 7 days or + 14 days in patients with complete blast clearance))
- Disease stabilization (DS)(until fifteen years after last UniCAR02-T administration)
- Complete (CR, CRh, CRi ) and partial remission (PR)(until fifteen years after last UniCAR02-T administration)
- Progression free survival (PFS)(until fifteen years after last UniCAR02-T administration)
- Overall survival (OS)(until fifteen years after last UniCAR02-T administration)
- Toxicity and efficacy in repeated cycles of TM123 administration(duration of consolidation cycle treatment)