TLD-1, a Novel Liposomal Doxorubicin, in Patients With Advanced Solid Tumors: A Multicenter Open-label Single-arm Phase I Trial
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 12
- 试验地点
- 5
- 主要终点
- Dose-limiting toxicity (DLT)
研究概览
简要总结
TLD-1 is a novel liposomal formulation of doxorubicin (PEG surface) that compared favorably to conventional liposomal formulations of doxorubicin including Caelyx® in preclinical in vivo models. Particle features including size, charge distribution, lipid composition and drug release add up to a considerably altered particle behavior compared to Caelyx®, potentially explaining the lack of hand-foot-syndrome in respective animal models. Preclinical evaluation confirmed TLD-1 to be a promising new and innovative formulation of doxorubicin with promising activity and good tolerability.
详细描述
Despite impressive progress in the fields of surgical and immunological cancer therapies, most late-stage cancer treatments still heavily depend on conventional chemotherapeutics, which are often effective but also toxic, resulting in severe adverse effects limiting the dose and duration of therapy. Consequently, there remains a high unmet medical need for new innovative systemic treatments with an improved risk-benefit-profile.
Doxorubicin is a potent anthracycline used as a systemic treatment against several solid tumor including breast, ovarian and bladder cancer, small cell lung cancer and various types of sarcoma. However, Doxorubicin use is often limited due to hematological and non-hematological toxicity including cumulative cardiotoxicity with myocardial damage.
Cardiotoxicity has been substantially mitigated through the introduction of liposomal formulations such as Myocet and Caelyx/Doxil. Both products are associated with substantially lower rates of cardiac dysfunction during or post-treatment. Whereas Myocet's clinical use remains limited due to the intricate "bedside" reconstitution process, Caelyx has been associated with a high incidence of Palmar-Plantar Erythrodysesthesia (PPE) (also called hand-foot-syndrome), likely due to its long plasma half-life.
The development of TLD-1 (Talidox) aimed at combining the cardio-preserving properties of the liposomal delivery system with shorter blood circulation time in order to reduce the risk of PPE. Even though the pathophysiology of PPE is not yet fully understood, studies analyzing the correlation of dose and pharmacokinetic parameters with PLD toxic effects revealed that the severity of PPE correlated significantly with plasma half-life (t1/2).
Given its performance in preclinical trials, TLD-1 bears the potential for an improved benefit/risk profile compared to established liposomal doxorubicin formulations including Caelyx.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
TLD-1
Duration of treatment
-
1 cycle: 21 days
-
1 cycle: 28 days (only comparative PK part, in cycle 1 or 2)
-
until progression or occurrence of unacceptable toxicity or withdrawal, but
-
maximum 9 cycles for patients previously not treated with anthracyclines
-
maximum 6 cycles for patients previously treated with anthracyclines.
-
Dose: i.v., according to DL on day 1 of each cycle or tentative MTD
干预措施: TLD-1 (Drug)
Caelyx (only for comparative PK part)
Duration of treatment
- 1 cycle: 28 days
- Caelyx is given only in one cycle (cycle 1 or 2)
- Dose: i.v., 40mg/m2
干预措施: Caelyx (Drug)
结局指标
主要结局
Dose-limiting toxicity (DLT)
时间窗: at 3 weeks
Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: Area under curve [Cmax]
时间窗: 2 months
Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: Terminal half life [t½]
时间窗: 2 months
Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: Ratio of unencapsulated to encapsulated drug over time for Caelyx and TLD-1
时间窗: 2 months
Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: volume of distribution [Vd]
时间窗: 2 months
Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: Area under curve [AUC]
时间窗: 2 months
Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: Clearance (CL)
时间窗: 2 months
次要结局
- Population pharmacokinetics: Area Under the Curve [AUC](at 2 months)
- Time to treatment failure (TTF)(at 7 months)
- Adverse Events (AEs)(at 7 months)
- Population pharmacokinetics (PK) of TLD-1: clearance (CL)(at 2 months)
- Population pharmacokinetics: Maximum Plasma Concentration [Cmax](at 2 months)
- Objective tumor response (OR)(at 7 months)
- Population pharmacokinetics (PK) of TLD-1: volume of distribution (Vd)(at 2 months)