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TLD-1, a Novel Liposomal Doxorubicin, in Patients with Solid Tumors: Comparative Pharmacokinetics and Final Results
Marian Klose1,2, Ilaria Colombo3, Katrin Gobat4
1Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 12169, Berlin, Germany.
Background And Objective:
Targeted liposomal doxorubicin (TLD-1) is a novel PEGylated liposomal doxorubicin (PLD) with optimized formulation characteristics, developed to improve the benefit-risk profile of PLD. This randomized intrapatient crossover amendment to the phase 1 SAKK 65/16 trial (NCT03387917) compared the pharmacokinetics (PK) of TLD-1 and Caelyx™ and included a pooled analysis of safety and preliminary antitumor activity at the recommended phase 2 dose (RP2D).
Methods:
Patients with advanced breast or platinum-resistant ovarian cancer in the comparative PK part were randomized to receive TLD-1 in cycle 1 and Caelyx™ in cycle 2, or vice versa, followed by TLD-1 thereafter. Both formulations were administered intravenously at 40 mg/m2 and PK was assessed using non-compartmental analysis. Safety and antitumor activity were analyzed across 23 patients treated with TLD-1 at the RP2D, including 13 from the comparative PK part and 10 from the published dose-escalation part.
Results:
In 10 evaluable patients from the comparative PK part, TLD-1 showed higher encapsulated doxorubicin exposure (AUC0-inf: 3222 vs 2139 mg·h/L) and longer median half-life (118 vs 70 h) than Caelyx™. Severe treatment-related events occurred in 43% of patients (10/23) in the full RP2D cohort, most commonly grade 3 palmar-plantar erythrodysesthesia, oral mucositis, and anemia (2 patients each). The investigator-assessed objective response rate was 8.7% (2/23), with partial responses in patients with breast cancer.
Conclusions:
Targeted liposomal doxorubicin demonstrated prolonged systemic circulation and low variability in liposomal drug release, likely due to its formulation characteristics. At 40 mg/m2 every 3 weeks, TLD-1 was well tolerated and showed modest preliminary antitumor activity in advanced breast cancer.
Gov Identifier:
NCT03387917, registered 2017-11-21.
Insights
Targeted liposomal doxorubicin (TLD-1) shows improved pharmacokinetics and tolerability compared to Caelyx™ in advanced cancers. This novel formulation offers prolonged circulation and modest antitumor activity, suggesting a better benefit-risk profile.
Area of Science:
- Pharmacology and Oncology
- Drug Delivery Systems
- Clinical Trials
Background:
- Pegylated liposomal doxorubicin (PLD) formulations aim to improve cancer treatment efficacy and safety.
- Targeted liposomal doxorubicin (TLD-1) is a novel PLD with optimized characteristics designed to enhance the benefit-risk profile of existing PLD therapies.
Purpose of the Study:
- To compare the pharmacokinetics (PK) of TLD-1 and Caelyx™ in patients with advanced breast or ovarian cancer.
- To evaluate the safety and preliminary antitumor activity of TLD-1 at the recommended phase 2 dose (RP2D).
Main Methods:
- A randomized intrapatient crossover design was used to compare TLD-1 and Caelyx™ PK in patients with advanced breast or platinum-resistant ovarian cancer.
- Pharmacokinetic parameters, including AUC0-inf and half-life, were assessed. Safety and antitumor responses were analyzed in patients receiving TLD-1 at the RP2D.
Main Results:
- TLD-1 demonstrated significantly higher encapsulated doxorubicin exposure (AUC0-inf: 3222 vs 2139 mg·h/L) and a longer median half-life (118 vs 70 h) compared to Caelyx™.
- The overall incidence of severe treatment-related adverse events was 43%, with common events including palmar-plantar erythrodysesthesia, oral mucositis, and anemia.
- An objective response rate of 8.7% was observed, with partial responses noted in breast cancer patients.
Conclusions:
- TLD-1 exhibits prolonged systemic circulation and minimal variability in liposomal drug release, attributed to its optimized formulation.
- At a dose of 40 mg/m² every 3 weeks, TLD-1 is well-tolerated and shows preliminary antitumor activity in advanced breast cancer, supporting its potential as an improved PLD option.
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