Phase I study of DFP-11207, a novel oral fluoropyrimidine with reasonable AUC and low C max and improved tolerability, i
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PHASE I STUDIES
Phase I study of DFP-11207, a novel oral fluoropyrimidine with reasonable AUC and low Cmax and improved tolerability, in patients with solid tumors Jaffer A. Ajani 1 & Milind Javle 1 & Cathy Eng 1 & David Fogelman 1 & Jackie Smith 1 & Barry Anderson 2 & Chun Zhang 3 & Kenzo Iizuka 3 Received: 31 July 2019 / Accepted: 15 April 2020 # The Author(s) 2020
Summary 5-fluorouracil (5-FU) and 5-FU derivatives, such as capecitabine, UFT, and S-1, are the mainstay of chemotherapy treatment for gastrointestinal cancers, and other solid tumors. Compared with other cytotoxic chemotherapies, these drugs generally have a favorable safety profile, but hematologic and gastrointestinal toxicities remain common. DFP-11207 is a novel oral cytotoxic agent that combines a 5-FU pro-drug with a reversible DPD inhibitor and a potent inhibitor of OPRT, resulting in enhanced pharmacological activity of 5-FU with decreased gastrointestinal and myelosuppressive toxicities. In this Phase I study (NCT02171221), DFP-11207 was administered orally daily, in doses escalating from 40 mg/m2/day to 400 mg/m2/day in patients with esophageal, colorectal, gastric, pancreatic or gallbladder cancer (n = 23). It was determined that DFP-11207 at the dose of 330 mg/m2/day administered every 12 hours was well-tolerated with mild myelosuppressive and gastrointestinal toxicities. The pharmacokinetic analysis determined that the 5-FU levels were in the therapeutic range at this dose. In addition, fasted or fed states had no influence on the 5-FU levels (patients serving as their own controls). Among 21 efficacy evaluable patients, 7 patients had stable disease (33.3%), of which two had prolonged stable disease of >6 months duration. DFP-11207 can be explored as monotherapy or easily substitute 5-FU, capecitabine, or S-1 in combination regimens. Keywords 5-FU derivative . Chemotherapy . Solid tumor . Dihydropyrimidine dehydrogenase
Introduction 5-Fluorouracil (5-FU), an antimetabolite, was introduced by Heidelberger et al. [1] in 1957, and has since been widely used as a single agent or in combination with other drugs [2–4] mainly in localized or metastatic gastrointestinal cancers and breast cancer. Clinical response and toxicity of 5-FU are remarkably influenced by its dosing schedule and a prolonged exposure by continuous infusion of 5-FU has been found to increase tumor response rates [5–12].
* Kenzo Iizuka [email protected] 1
Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2
Theradex, Princeton, NJ, USA
3
Delta-Fly Pharma, Inc., Tokushima, Japan
Seeking the efficacy advantage of a continuous infusion 5FU schedule and in order to enhance patient compliance [13, 14], several oral 5-FU derivatives such as capecitabine [15], tegafur-uracil (UFT) [16] and tegafur-gimeracil-oteracil (S-1) [17] have been developed. Available oral fluoropyrimidines, although considered efficacious have toxicities that remain an ongoing concern. Th
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