Development Of Novel Antimetabolite, Dfp-11207, With Self-Toxicity Protection And Its Promising Preclinical And Clinical Profiles

Background: For over 50 years, 5-fluorouracil (5-FU) has played a critical role in the systemic chemotherapy of various gastrointestinal cancers including gastric, colorectal and pancreatic cancer which are the leading causes of cancer death globally. Although systemic cytotoxics such as 5-FU can modestly prolong overall survival in the adjuvant and advanced settings, but at the cost of unpleasant toxicities. Therefore better drug formulations are desirable. Methods: To this end, we developed a new conceptual fluoropyrimidine, DFP-11207 that is engineered to reduce toxicity without loss of antitumor activity as well in addition to providing sustained concentrations of the active anticancer moiety. DFP-11207 contains three components in one formulation: 1-ethoxymethyl-5-fluorouracil (EM-FU) as a prodrug of 5-FU, 5-chloro-2,4-dihyroxypyridine (CDHP) as a potent inhibitor of 5-FU degradation and cytrazinic acid (CTA) as a gastrointestinal regulator of 5-FU phosphorylation. Results: In in vitro metabolism studies using cell-free extracts from plasma, liver and tumors or intact tumor cells, DFP-11207 was rapidly hydrolyzed to 3 components and subsequently EM-FU was specifically converted to 5-FU by liver microsomes, and CDHP and CTA strongly inhibited 5-FU degradation and phosphorylation, respectively. Following consecutive oral administration to human tumor-bearing nude rats, DFP-11207 attained favorable antitumor efficacy and long-sustained PK profiles with lack of GI- and myelo-toxicities. Next, in investigational clinical study in patients with solid tumors, 12 patients were treated at 8 unique dose levels of DFP-11207, ranging from 40 to 440mg/m2/day by each 1 pt. MTD and RD of daily and 28-day consecutive DFP-11207 was found to be 440 (n=2) and 330 mg/m 2 (n=6), respectively. The main AEs were nausea,, anemia, neutropenia, febrile neutropenia but these events were very mild, and no thrombocytopenia was observed as expected. Furthermore, review of the preliminary PK data, DFP-11207 at 330 mg/m 2 resulted in a desirable low but efficacious (~15- 30 ng/ml) steady-state plasma concentration of 5-FU. Interestingly, some of patients heavily treated with therapeutic drugs had a stable-disease for long periods. Conclusion: Our preclinical and early clinical data with DFP-11207 suggest that it’s a promising compound for the treatment of gastrointestinal cancers and can overcome the shortcomings of all other oral fluoropyrimidines. Citation Format: Masakazu Fukushima, Kenzo Iizuka, Kokoro Eshima, Chung Zhang, Cheng Jin, Kiyoshi Eshima, Jaffer Ajani. Development of novel antimetabolite, DFP-11207, with self-toxicity protection and its promising preclinical and clinical profiles [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 5099. doi:10.1158/1538-7445.AM2017-5099