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, Milind Javle, Cathy Eng, David Fogelman, Jackie Smith, Barry Anderson, Chun Zhang, Kenzo Iizuka, Jaffer A Ajani, Milind Javle, Cathy Eng, David Fogelman, Jackie Smith, Barry Anderson, Chun Zhang, Kenzo Iizuka

Abstract

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; Dihydropyrimidine dehydrogenase; Solid tumor.

Conflict of interest statement

Jaffer Ajani declares receiving grants/research support from Delta-Fly Pharma, Inc., ProLynx, Bristol-Myers Squibb, Merck, Astellas, Roche, Zymeworks, Eli Lilly, Taiho Pharmaceutical, and honoraria or consultation fees from Bristol-Myers Squibb, Merck, Astellas, Eli Lilly, AstraZeneca, Daiichi Sankyo, Roche. Milind Javle declares receiving honoraria or consultation fees from Rafael Pharmaceuticals, Incyte, Pieris Pharmaceuticals, Merck, Novartis, Seattle Genetics, BeiGene, QED Therapeutics, Bayer. Cathy Eng declares that she has no conflict of interest. David Fogelman declares receiving grants / research support from Delta-Fly Pharma, Inc. Jackie Smith declares that she has no conflict of interest. Barry Anderson declares that he has no conflict of interest. Chun Zhang is an employee of Delta-Fly Pharma, Inc. Kenzo Iizuka is an executive officer of Delta-Fly Pharma, Inc.

Figures

Fig. 1
Fig. 1
Disposition of patients (N = 23)
Fig. 2
Fig. 2
PK Parameters in food effect study (N = 6)

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