Background and Objective <p>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).</p> Methods <p>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.</p> Results <p>In 10 evaluable patients from the comparative PK part, TLD-1 showed higher encapsulated doxorubicin exposure (AUC_0–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.</p> Conclusions <p>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.</p> ClinicalTrials.gov Identifier <p>NCT03387917, registered 2017-11-21.</p>