Abstract 5112: Evaluation of FF-10502-01, a new pyrimidine nucleoside analogue, in pancreatic (PANC) patient-derived xenograft (PDX) models compared to gemcitabine and in combination with nab-paclitaxel
Authors: Suzuki Takeaki , Paradiso Linda J. , Ricono Jill , Nakashima Jonathan , Iwaki Yoshihide , Mima Shinji , Yamada Takayuki , Kakinuma Chihaya , Iwamura Hiroyuki , Watanabe Shinichi 
Published: July 2017

Introduction

FF-10502-01 is a synthetic pyrimidine nucleoside analogue structurally similar to gem with a substitution of sulfur for oxygen in the pentose sugar. In previous studies, FF-10502-01 demonstrated preclinical efficacy across multiple solid tumors, including PANC cancer. In this study, we investigated the anti-tumor effect of FF-10502-01 in PANC PDX models.

Methods

10 PANC PDX tumors were sourced from primary (2) or metastatic sites (8). 7 demonstrated high resistance (HR) to gem, 1 intermediate, and 2 low. In the dose-finding study, 3 PDX models were studied in 9 grps of NOD-SCID mice (n=10/grp), treated with 240 or 480 mg/kg FF-10502-01, 3 or 6 mg/kg nab-pac or 240 mg/kg gem, alone and in combination for 28d, followed by 28d observation. The definitive study consisted of 7 PDX models. 6 grps (n=10/grp) were treated with 240 or 480 mg/kg FF-10502-01, 6 mg/kg nab-pac or 240 mg/kg gem, alone and/or in combination for 28d, followed by 28d observation. After subcutaneous transplantation, animals were left undisturbed for 7d. Animals were monitored weekly and tumor volume measured with calipers. Average tumor volume (mm3) for each group at randomization into treatment grps ranged from 184.34 – 199.51 (SD ± 20.94 – 30.40). Statistical significance was determined using one-way ANOVA and Tukey’s test.

Results

At clinically relevant doses, FF-10502-01, alone and in combination with nab-pac demonstrated greater tumor growth suppression than vehicle-treated animals (p≤0.0001). In 7 models, FF-10502-01/nab-pac demonstrated higher tumor growth suppression than gem/nab-pac (p≤0.5, p≤0.01 or p≤0.001), irrespective of resistance to gem. In 3 models, there was no difference, but these models were highly responsive to gem/nab-pac, thus minimizing the effects of FF-10502-01/nab-pac. Despite statistical insignificance, FF-10502-01/nab-pac still demonstrated greater tumor growth inhibitory activity to gem/nab-pac. In HR gem models, FF-10502-01 was superior to gem (p≤0.0001, p≤0.001, p≤0.05) in 3 of 7, and FF-10502-01/nab-pac was superior to gem/nab-pac in 6 of 7 (p nab-pac (p≤0.0001, p≤0.0001, p≤0.01, p≤0.05). FF-10502-01/nab-pac also was more tolerable than gemcitabine/nab-pac, as demonstrated by less weight loss.

Conclusions

FF-10502-01 is a new pyrimidine nucleoside analogue with demonstrated preclinical efficacy in solid tumors, including PANC cancer. In PANC PDX models, FF-10502-01 alone and in combination with nab-pac demonstrated higher efficacy and better tolerability than gem alone or gem/nab-pac. FF-10502-01 is in Phase 1 clinical development.

Citation Format: Takeaki Suzuki, Linda J. Paradiso, Jill Ricono, Jonathan Nakashima, Yoshihide Iwaki, Shinji Mima, Takayuki Yamada, Chihaya Kakinuma, Hiroyuki Iwamura, Shinichi Watanabe. Evaluation of FF-10502-01, a new pyrimidine nucleoside analogue, in pancreatic (PANC) patient-derived xenograft (PDX) models compared to gemcitabine and in combination with nab-paclitaxel [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 5112. doi:10.1158/1538-7445.AM2017-5112