TLD-1, a Novel Liposomal Doxorubicin, in Patients with Solid Tumors: Comparative Pharmacokinetics and Final Results of a Multicenter Phase 1 Study (SAKK 65/16).

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.