Shinji Hagiwara

A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations

An activating mutation of Fms-like tyrosine kinase 3 (FLT3) is the most frequent genetic alteration associated with poor prognosis in acute myeloid leukemia (AML). Although many FLT3 inhibitors have been clinically developed, no first-generation inhibitors have demonstrated clinical efficacy by monotherapy, due to poor pharmacokinetics or unfavorable safety profiles possibly associated with low selectivity against FLT3 kinase. Recently, a selective FLT3 inhibitor, quizartinib, demonstrated favorable outcomes in clinical studies. However, several resistant mutations emerged during the disease progression. To overcome these problems, we developed a novel FLT3 inhibitor, FF-10101, designed to possess selective and irreversible FLT3 inhibition. The co-crystal structure of FLT3 protein bound to FF-10101 revealed the formation of a covalent bond between FF-10101 and the cysteine residue at 695 of FLT3. The unique binding brought high selectivity and inhibitory activity against FLT3 kinase. FF-10101 showed potent growth inhibitory effects on human AML cell lines harboring FLT3 internal tandem duplication (FLT3-ITD), MOLM-13, MOLM-14, and MV4-11, and all tested types of mutant FLT3-expressing 32D cells including quizartinib-resistant mutations at D835, Y842, and F691 residues in the FLT3 kinase domain. In mouse subcutaneous implantation models, orally administered FF-10101 showed significant growth inhibitory effect on FLT3-ITD-D835Y- and FLT3-ITD-F691L-expressing 32D cells. Furthermore, FF-10101 potently inhibited growth of primary AML cells harboring either FLT3-ITD or FLT3-D835 mutation in vitro and in vivo. These results indicate that FF-10101 is a promising agent for the treatment of patients with AML with FLT3 mutations, including the activation loop mutations clinically identified as quizartinib-resistant mutations.

Abstract 5148: Liposomal gemcitabine, FF-10832, improves gemcitabine (GEM) pharmacokinetics (PK) and increases anti-tumor efficacy

Introduction: FF-10832 is a liposome suspension optimized by Fujifilm nanotechnology containing 0.5 mg/mL GEM, cholesterol, HSPC, N-MPEG-DSPE. FF-10832 is expected to improve GEM PK and have strong anti-tumor effects. The PK and anti-tumor effects of FF-10832 were studied in mice and human pancreatic cancer xenograft models. Methods: Single-dose murine plasma PK of FF-10832 1 mg/kg was compared to GEM 240mg/kg. In vivo activity of GEM 240 mg/kg and FF-10832 1-5 mg/kg IV once weekly were compared in human pancreatic cancer murine xenograft models; 2 subcutaneous (Capan-1 [GEM-sensitive] and BxPC-3 [GEM-resistant]), and 1 orthotopic (SUIT-2) model. The active form of GEM (GEM triphosphate [dFdCTP]) inhibits DNA synthesis. dFdCTP tissue concentrations following FF-10832 4mg/kg and GEM 240mg/kg were compared in these models. Results: An extended plasma t ½ (10.6 vs. 2.9 hours), lower clearance, and smaller volume of distribution were observed with FF-10832 vs. GEM, which correlated with greater dose exposure achieved with FF-10832 compared to GEM (AUC last 186000 vs. 73000 hr·ng/mL). FF-10832 demonstrated increased in vivo activity in SUIT-2, Capan-1, and BxPC-3 models at significantly lower doses compared to GEM. In the Capan-1 and BxPC3 models, FF-10832 showed dose-dependent tumor growth suppression with FF-10832 4 mg/kg and 5 mg/kg superior to that of GEM (p Conclusions: FF-10832 is a stable liposomal GEM formulation demonstrating potent anti-tumor efficacy in solid tumor models with a favorable pharmacokinetic profile compared to non-liposomal GEM. Increased exposure achieved at lower GEM doses may potentially result in superior efficacy and a more tolerable safety profile for FF-10832 compared to non-liposomal GEM. Citation Format: Takeshi Matsumoto, Tsukasa Kitahashi, Takashi Komori, Hiromu Kitahara, Kohei Ono, Naoki Yamada, Hiroyuki Iwamura, Kiyohito Takada, Shinji Hagiwara, Yasuhiro Shimada. Liposomal gemcitabine, FF-10832, improves gemcitabine (GEM) pharmacokinetics (PK) and increases anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5148. doi:10.1158/1538-7445.AM2017-5148