Oraxol consists of oral paclitaxel administered with the novel P-glycoprotein inhibitor HM30181A which enables the oral absorption of paclitaxel. Ramucirumab (RAM) + intravenous paclitaxel is FDA approved 2nd line treatment of gastric cancer. Oraxol 200mg/m2 days 1-3, weekly has similar exposure to weekly paclitaxel 80/m2 intravenously. This study was to determine the maximum tolerated dose (MTD) of Oraxol + RAM.
17 patients with gastric or esophageal cancers who failed prior fluoropyrimidine or platinum containing chemotherapies were studied. Dose escalation followed the standard 3 + 3 design: Cohort 1: Oraxol 200mg/m2 days 1-3, weekly. Cohort 2: Oraxol 250mg/m2 days 1-3, weekly. Cohort 3: Oraxol 300mg/m2 days 1-3, weekly. RAM 8 mg/kg IV every 2 weeks was co-administered in all patients. Dose limiting toxicity (DLT) were assessed by week 4. Adverse events (AEs) were assessed per CTCAE v4.03 and response by RECIST v1.1.
Cohort 1: One febrile neutropenia (DLT) occurred in 6 patients. Partial response (PR)=2/6, stable disease (SD)=1/6 and progressive disease (PD)=3/6. Cohort 2: One grade-3 neutropenia with treatment delay (DLT) occurred in 7 pts. PR = 3/6 and PD = 3/6 in 6 evaluable patients. Cohort 3: Two DLT (febrile neutropenia and grade-3 gastric hemorrhage) occurred in 3 patients. The MTD of Oraxol was 300mg/m2 days 1-3, weekly in combination with RAM. All patients in this study had complete recovery of their DLT. Oraxol PK did not increase significantly in Cohort-2 and Cohort-3.
Based on the lack of significant increase in exposure to Oraxol at higher doses, with similar efficacy and DLT in Cohorts 1 and 2, an extension study using Oraxol 200mg/m2 Days 1-3, weekly + Ramucirumab 8 mg/kg every 2 weeks as in Cohort-1 is initiated.
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All authors have declared no conflicts of interest.