Phase I study of DFP-11207, a novel oral 5-FU with enhanced PK and improved tolerability, in patients with solid tumors.

person Jaffer A. Ajani The University of Texas MD Anderson Cancer Center, Houston, TX info_outline Jaffer A. Ajani, Milind M. Javle, Cathy Eng, David R. Fogelman, Barry Douglas Anderson, Chun Zhang, Kenzo Iizuka

Authors person Jaffer A. Ajani The University of Texas MD Anderson Cancer Center, Houston, TX info_outline Jaffer A. Ajani, Milind M. Javle, Cathy Eng, David R. Fogelman, Barry Douglas Anderson, Chun Zhang, Kenzo Iizuka Organizations The University of Texas MD Anderson Cancer Center, Houston, TX, University of Texas MD Anderson Cancer Center, Houston, TX, Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, Theradex, Princeton, NJ, Delta-Fly Pharma, Inc., Tokushima, Japan Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: DFP-11207 combines a 5-fluorouracil (5-FU) pro-drug with a reversible dihydropyrimidine dehydrogenase inhibitor and a potent inhibitor of orotate phosphoribosyl transferase resulting in enhanced pharmacological activity of 5-FU with decreased gastrointestinal and myelosuppressive toxicity. Methods: Patients with advanced solid tumors were treated in this single arm, dose escalation study. Accelerated dose escalation using single pt cohorts was followed until drug-related Gr2 adverse events occurred; then a 3+3 design was followed to determine maximum tolerated dose (MTD). Pts were dosed daily in 28-day cycles until intolerable toxicity or disease progression. PK sampling was performed for DFP-11207 metabolites on all pts and a 6 pt cohort received DFP-11207 in fed and fasted states to determine drug bioavailability. Results: Primary tumors among the 23 enrolled pts included esophageal, colorectal, gastric, pancreatic and gallbladder. Seventeen pts were treated at 8 dose levels of oral DFP-11207 administered daily, ranging from 40 to 440 mg/m 2 /d. At 440 mg/m 2 /d one pt experienced drug-related Gr3 dehydration and mucosal inflammation, and Gr4 febrile neutropenia; a second pt experienced Gr4 febrile neutropenia. One DLT of Gr3 vomiting occurred among 6 pts treated at 330 mg/m 2 /d dosed q12hrs confirming the MTD. Six pts were administered 300 mg DFP-11207 q12 hrs in a fed or fasted state to determine drug bioavailability. Among all pts, the most frequently reported drug-related TEAEs were fatigue (47.8%), nausea (47.8%), decreased appetite (39.1%), diarrhea (26.1%), vomiting (21.7%), anemia (13.0%), dysgeusia (13.0%), mucosal inflammation (13.0%) and palmar-plantar erythrodysaesthesia syndrome (13.0%). PK analyses of pts treated at 330 and 440 mg/m 2 /d indicate 5-FU concentrations of ~20 ng/mL throughout the dose cycle. There was no substantial difference in DFP-11207 bioavailability among pts in a fed or fasted state. Out of 21 efficacy evaluable pts, 7 pts had stable disease (33.3%), of which 2 had prolonged stable disease of > 6 months. No pts achieved CR or PR. Conclusions: DFP-11207 at the dose of 330 mg/m 2 /d q12hrs is well-tolerated in pts with solid tumors with mild myelosuppressive and gastrointestinal side effects, and results in circulating 5-FU levels conducive to an anti-tumor effect. DFP-11207 can be explored as monotherapy or substitute for 5-FU, capecitabine or S-1 in combination treatment regimens. Clinical trial information: NCT02171221