A Phase I/II trial of fruquintinib in combination with paclitaxel for second-line treatment in patients with advanced gastric cancer.

128 Background: Advanced gastric cancer (AGC) is a major problem particularly in Asian countries. The treatment options are limited after standard first line chemotherapy. This phase I/II study aimed to evaluate the tolerability, pharmacokinetics and preliminary efficacy of fruquintinib, a selective oral VEGFR inhibitor, combined with paclitaxel as second-line therapy in Chinese patients with AGC. Methods: This open arm phase I/II trial (NCT02415023) consisted of dose finding and dose expansion stages. In the dose finding stage, 3 dose levels of fruquintinib (2, 3, 4 mg; once daily for 3 weeks) were evaluated in combination with standard 80 mg/m2 paclitaxel (once weekly on Days 1, 8 and 15) in a 28-day cycle until the maximum tolerated dose or recommended phase II dose (RP2D) was reached. Additional patients were enrolled at the RP2D to further assess the efficacy, safety and pharmacokinetic profile. Results: As of Sept. 10, 2016, a total of 32 patients were enrolled including 15 during dose escalation. The RP2D regimen was determined to be fruquintinib 4mg daily combined with paclitaxel 80mg/m2 weekly for 3 weeks followed by 1 week off in a 4 week cycle. Two patients at 4mg experienced dose-limiting toxicity, both with febrile neutropenia. The grade 3 or 4 treatment emergent adverse events were neutropenia (40.6%), leukopenia (28.1%), decreased hemoglobin (6.25%), hand-foot skin reaction (6.25%), neurophlegmon (6.25%), and hypertension (6.25%), more frequent in the 4mg cohort. At steady state, Fruquintinib AUC (AUC ss ) increased dose-proportionally and within the historic range as a single agent, while paclitaxel exposure, at the RP2D regimen, increased by approximately 30% compared to the AUC prior to fruqintinib dosing. Twenty-eight of 32 patients were evaluable for response, and of these, 10 patients had partial response (Objective Response Rate = 35.7%), 9 patients experienced stable disease for at least 8 weeks (Disease Control Rate = 67.9%). At RP2D, ≥ 16w-PFS = 50% and ≥ 7m-OS = 50%. Conclusions: Combination of fruquintinb and paclitaxel appeared to be generally well-tolerated with promising tumor response. Further evaluation in a controlled phase II study is warranted. Clinical trial information: NCT02415023.