A phase 1, first-in-human, dose-escalation and biomarker trial of liposomal gemcitabine (FF-10832) in patients with advanced solid tumors.
Authors: Borazanci Erkut Hasan , Janku Filip , Hamilton Erika P. , Thomas Jacob Stephen , Sen Shiraj , Fu Siqing , Wheeler Catherine A. , Wages David S. , Matsumoto Takeshi , Shimoyama Susumu , Yamada Naoki , Subach Ruth Ann , Madden Timothy , Johansen Mary , Maier Gary , Cheung Kin , Korn Ron , Falchook Gerald Steven 
Published: June 2022

3097 Background: FF-10832 is a stable liposomal formulation of gemcitabine (GEM) shown to overcome resistance through increased plasma stability and enhanced tumor drug delivery. Macrophage uptake and immune activation in the tumor microenvironment (TME) play a role in the superior efficacy of FF-10832 compared to GEM, with selective, marrow-sparing biodistribution contributing to an improved safety profile. Methods: A 3+3 design determined the safety, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics (PK), and recommended Phase 2 dose (RP2D). FF-10832 was administered IV once or twice per cycle on a 28 or 21-day schedule until disease progression or unacceptable toxicity. Circulating immune cell populations were measured over time by flow cytometry. Results: Patients (pts) [n = 73, 26M/47F; median age, 64 (range, 26–84); # prior therapies, 3 (1–11); prior GEM, 60%] received FF-10832 on Day 1 and 15 Q28 days (1.2–30 mg/m2), Day 1 and 8 Q21 days (12–23 mg/m2), or Day 1 only Q28 or 21 days (30–55 mg/m2); median # cycles = 2 (1–14) & time on study = 8.3 (4–60) weeks. Common drug-related adverse events were Grade (Gr) ≤2 rash (22%), nausea (22%, 1 Gr 3), and pyrexia (21%, 2 Gr 3). Dose-limiting Gr ≥3 cellulitis/skin ulcers were observed at ≥23 mg/m2 with twice per cycle dosing and those regimens discontinued. Dose frequency was reduced to Day 1 only, which was well-tolerated without significant skin toxicity. Gr ≥3 thrombocytopenia and pneumonitis were observed at 55 mg/m2 Q21 days and the MTD confirmed at 40 (Q21) and 48 mg/m2 (Q28). Median OS = 25.3 (95%CI: 16–27.1) weeks and PFS = 9.6 (95%CI: 7.9–17.6) weeks. Three of 35 evaluable pts achieved a partial response (PR): one pt with gallbladder cancer who previously progressed on GEM achieved a 50%↓ by Cycle 13 at 40 mg/m2 Q28 days & maintains response on study at 60 weeks; two pts with pancreatic cancer had ≥30%↓: one adenocarcinoma after 2 cycles at 4.8 mg/m2 Days 1 & 15 Q28 days, and one acinar cell after 7 cycles at 40 mg/m2 Q28 days who remains on study. Stable disease (SD) was observed in 16 pts; 9 for ≥20 weeks. AUC increased in proportion to dose without accumulation. An extended plasma t1/2 (hrs) for released (39) & total GEM (26) with a free fraction < 1% of total GEM concentrations suggests continuous release in the TME. Pts with PR or SD had dose and time-related log decreases in Ki67+ regulatory T cells relative to total CD4+ cells with increases in anti-tumor CD8+ cells, suggesting a shift to a more immunocompetent environment. Conclusions: FF-10832 was well-tolerated in heavily pre-treated pts with solid tumors, with evidence of anti-tumor activity in pts who progressed on prior GEM. Prolonged, continuous exposure and enhancement of anti-tumor immunity may contribute to improved efficacy. Expansion is ongoing in biliary tract cancer pts treated at the RP2D/schedule of 40 mg/m2 Day 1 of a 21-day cycle. Clinical trial information: NCT03440450.