Background: FF-10850 (liposomal topotecan) was developed using a unique dihydrosphingomyelin-based carrier to enhance tumor drug delivery and retention, leading to improved efficacy and safety. Preclinical studies demonstrated superior anti-tumor activity with less myelosuppression compared to topotecan, with a pharmacokinetic (PK) profile supporting a twice-monthly dosing schedule. Methods: Accelerated titration followed by a 3+3 dose escalation design was used to determine the safety, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), PK, and recommended Phase 2 dose. FF-10850 was administered IV on Day 1 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Results: Patients (pts) [n = 29; 4M/25F; median age, 64 (range, 37–79) and # prior therapies, 4 (range, 1–8)] received FF-10850 at doses of 1, 2, 2.5, 3, 3.5 and 5 mg/m²; median # of cycles, 2 (range, 1–11). FF-10850 was well-tolerated at doses up to 2 mg/m². Common drug-related adverse events (AEs) included anemia (83%, 51% Gr≥3), thrombocytopenia (62%, 35% Gr≥3), neutropenia (59%, 45% Gr≥3), nausea (38%), fatigue (24%, 7% Gr≥3), alopecia (24%), and hypokalemia (17%, 3% Gr≥3). Dose-limiting Gr≥3 thrombocytopenia, neutropenia, anemia, and fatigue were observed at doses ≥2.5 mg/m². Eight pts required dose reductions due to AEs. The median time on study was 8.3 (1.6–45) weeks, with a median PFS of 9.4 weeks and median OS at least 26 weeks. Of 24 pts evaluable for response, two achieved a partial response (PR). One pt with ovarian cancer treated at 3.5 mg/m² achieved a complete response in target lesions by Cycle 2 with stable non-target lesions, and maintained response for > 30 weeks (8 cycles) before progressing; dose was reduced in this pt to 2.6 mg/m² at Cycle 2 due to Gr 4 thrombocytopenia. Another pt with refractory metastatic Merkel cell carcinoma tolerated therapy well at 2 mg/m² and achieved a 48% reduction in target lesions that was maintained for > 30 weeks (8 cycles). Stable disease was observed in an additional 9 pts for ≥10 weeks (5 ovarian, 2 uterine and 2 cervical); five who maintained disease control for ≥24-45 weeks including one (ovarian) who had previously progressed on topotecan. An extended plasma t_1/2 for topotecan of 25-30 hours was observed with no apparent dose-dependency or accumulation; < 1% of circulating topotecan was in the free (released) form. Conclusions: FF-10850 was well-tolerated up to 2 mg/m² with anti-tumor activity demonstrated in heavily pre-treated pts with solid tumors including ovarian cancer, and an improved PK profile allowing less frequent dosing compared to topotecan. Expansion is ongoing in pts with ovarian and Merkel cell carcinoma at the RP2D of 2 mg/m² IV on Day 1 & 15 of a 28-day cycle. Clinical trial information: NCT04047251.