TLD-1, a Novel Liposomal Doxorubicin, in Patients With Advanced Solid Tumors
- Registration Number
- NCT03387917
- Lead Sponsor
- Swiss Group for Clinical Cancer Research
- Brief Summary
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.
- Detailed Description
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.
This first-in-human phase-I trial will evaluate the safety and will establish the maximal tolerated dose (MTD) and recommended phase II dose of TLD-1, and characterize specific dose limiting toxicities (DLT) of TLD-1. Moreover, the trial shall yield information on adverse events profile, pharmacokinetics and preliminary efficacy.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 12
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description TLD-1 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 Caelyx (only for comparative PK part) Caelyx Duration of treatment * 1 cycle: 28 days * Caelyx is given only in one cycle (cycle 1 or 2) * Dose: i.v., 40mg/m2
- Primary Outcome Measures
Name Time Method Dose-limiting toxicity (DLT) at 3 weeks Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: Area under curve [Cmax] 2 months Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: Terminal half life [t½] 2 months Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: Ratio of unencapsulated to encapsulated drug over time for Caelyx and TLD-1 2 months Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: volume of distribution [Vd] 2 months Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: Area under curve [AUC] 2 months Descriptive pharmacokinetics (PK) of TLD-1 vs Caelyx: Clearance (CL) 2 months
- Secondary Outcome Measures
Name Time Method 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
Trial Locations
- Locations (5)
Istituto Oncologico della Svizzera Italiana
🇨🇭Bellinzona, Switzerland
Inselspital Bern
🇨🇭Bern, Switzerland
Kantonsspital Graubünden
🇨🇭Chur, Switzerland
Kantonsspital St. Gallen
🇨🇭St. Gallen, Switzerland
Kantonsspital Winterthur
🇨🇭Winterthur, Switzerland