Phase I study of oral metronomic gemcitabine (D07001) in patients with advanced solid tumors

D07001-F4 is an absorption-enhanced oral gemcitabine developed in liquid formulation and adjusted to D07001-softgel capsules. We conducted 2 phase 1 studies to evaluate the dose-limiting toxicity (DLT), pharmacokinetics (PK), and maximum tolerated dose (MTD) of the 2 formulations of D07001 in patients with advanced solid tumors.

Initially, patients received escalating doses (2-80 mg) of D07001-F4 thrice a week for 2 weeks, followed by 1-week rest. Since no DLT was observed in the phase 1 study, the phase 1b study was conducted with D07001-softgel capsules (dose range: 40-120 mg) in patients with refractory gastrointestinal malignancies. A bridging dose of 40 mg was administered in the phase 1b study to achieve an equivalent intake of 80 mg of D07001-F4.

Fifty-three patients (phase 1, n = 34; phase 1b, n = 19) were enrolled. The mean oral bioavailability of D07001-F4 was ~39%. Two patients receiving 120 mg of D07001-softgel capsules experienced grade 3 hepatotoxicity and anorexia, respectively. Therefore, an additional 100 mg dose was tested and determined as the MTD. The Cmax and area under the curve of gemcitabine and its metabolite, 2', 2'-difluoro deoxyuridine, have a dose-dependent manner and comparable between the 2 formulations. Grade ≥ 3 anorexia (10.5%) and diarrhea (10.5%) were observed in the phase 1b extension study.

Our study demonstrated that D07001-softgel capsules can be safely administered as continuous dosing of up to 100 mg in patients with advanced solid tumors. Further studies are warranted to determine the appropriate dose in combination with other chemotherapy drugs.