Phase I study of DFP-11207, a novel oral fluoropyrimidine with reasonable AUC and low C max and improved tolerability, in patients with solid tumors

• Published in: Investigational new drugs Vol. 38; no. 6; p. 1763
• Main Authors: Ajani, Jaffer A, Javle, Milind, Eng, Cathy, Fogelman, David, Smith, Jackie, Anderson, Barry, Zhang, Chun, Iizuka, Kenzo
• Format: Journal Article
• Language: English
• Published: United States 01.12.2020
• Subjects: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - pharmacokinetics; Area Under Curve; Female; Fluorouracil - blood; Food-Drug Interactions; Humans; Hydrocarbons, Fluorinated - administration & dosage; Hydrocarbons, Fluorinated - adverse effects; Hydrocarbons, Fluorinated - pharmacokinetics; Male; Middle Aged; Neoplasms - blood; Neoplasms - drug therapy; Neoplasms - metabolism; Prodrugs - administration & dosage; Prodrugs - adverse effects; Prodrugs - pharmacokinetics; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - pharmacokinetics; Treatment Outcome; Solid tumor; Chemotherapy; Dihydropyrimidine dehydrogenase; 5-FU derivative
• ISSN: 1573-0646
• DOI: 10.1007/s10637-020-00939-w

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/m /day to 400 mg/m /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/m /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.