A phase I/II study of DHP107, a novel oral paclitaxel formulation, in patients with advanced solid tumors (phase I) and gastric cancer (phase II).

101 Background: Paclitaxel has been proven to be effective and widely used in various types of cancers. DHP107 is a novel oral paclitaxel formulation. In the previous first-in-human study, DHP107 showed no DLTs at a single dose-escalating schedule and was reported safe and feasible in patients with advanced malignancies. This study was conducted to determine 1) recommended dose (RD) for multiple dosing of DHP107 in patients with metastatic solid tumor and 2) efficacy in patients with advanced gastric cancer (AGC). Methods: In phase I study, standard 3 + 3 dose escalation scheme was used, and the planned dose of DHP107 was 150 mg/m 2 bid at level 1, 200 mg/m 2 bid at level 2, and 250 mg/m 2 bid at level 3 on days 1, 8, and 15, every 4 weeks. In phase II study planned by Simon’s optimal two stage design (P 0 =0.05, P 1 =0.25, α=0.05, and β=0.2), DHP107 was administered at the RD in patients with AGC refractory to first-line chemotherapy containing fluoropyrimidine and platinum. Results: In the phase I study, no dose-limiting toxicity (DLT) was observed at level 1 (n=3) and at level 2 (n=6). At level 3, 2 out of 4 patients showed a DLT (one grade 4 neutropenia over 7 days and one febrile neutropenia). At additional dose level 2A (225 mg/m 2 bid), 2 out of 4 patients experienced febrile neutropenia. Finally, the RD of DHP107 was determined as level 2 (200 mg/m 2 bid). In PK analysis, 200 mg/m 2 bid of DHP107 showed similar AUC, C max and half-life to i.v. paclitaxel at 80 mg/m 2 . Out of the 11 patients enrolled in the phase II study, 3 patients achieved a confirmed partial response (27%; 95% C.I. 0-59%). Grade 3/4 adverse events with frequency > 5% included neutropenia (27.3%), stomatitis (18.2%), anemia (9.1%), and febrile neutropenia (9.1%). There was no treatment-related death. Conclusions: RD of DHP107 was determined as 200 mg/m 2 bid. At the RD, DHP107 was generally well tolerated and showed anti-tumor activity comparable to i.v. paclitaxel as a second-line chemotherapy in AGC. Based on these results, a phase III study to compare DHP107 with i.v. paclitaxel is currently ongoing in AGC. This study was supported by DAEHWA Pharmaceutical Co. and Gangwon Institute for Regional Program Evaluation by Korean government.