First in human phase I study of chlorogenic acid injection in recurrent high grade glioma.

e14081 Background: Chlorogenic acid (CHA) is a natural product with good antitumor activity in preclinical study. A phase I clinical trial of CHA injection was conducted to determine tolerance, safety, pharmacokinetics in patients with recurrent high grade glioma. Methods: Patients received CHA injection intramuscularly once daily for 30 days of each cycle following continuous treatment extension based on clinical evaluation. A standard 3+3 design was used for dose-escalation. The primary endpoints were to evaluate the tolerance and safety of CHA, determine the maximum-tolerate dose (MTD) and dose-limiting toxicity (DLT). The secondary endpoints included:pharmacokinetics, preliminary antitumor efficacy and potential biomarkers. Results: Twenty-six patients were enrolled at five doses: 2mg/kg (3), 3mg/kg (9), 4mg/kg (9), 5.5mg/kg (3) and 7mg/kg (2). Two patients were discontinued during treatment due to muscle-related injection induration and one patient was discontinued due to compliance. Among 26 patients for DLT evaluation, two DLTs were observed muscle-related injection induration. The MTD was determined as 5.5mg/kg. Common adverse events included thrombocytopenia (3.84%), pain in flank, shoulder and arms (each 3.84%), and muscle-related injection induration (92.3%). The maximum plasma concentration of CHA was increased after administration at all doses . The elimination half-life ranged from 1.12 to 1.27 h on day 1 and from 1.19 to 1.39 h on day 30. The disease control rate of 1 month and 3 months were 52.17% (SD, 12) and 33.33% (SD, 6), respectively. By the end of Feb. 6th, 2018 , the median OS in dose 2mg/kg is 9.6 months, 9.4 months in dose 4mg/kg, 12.2 months in dose 5.5mg/kg. In 3mg/kg dose 7/9 patients are still alive, two of them survival over 18 months since adminstration. In 5.5mg/kg dose 2/3 patients are survival. Among over 13 serum cytokines, IL12p70, IL-28A and IL-27 were identified to predict for both T cell immune response to CHA and clinical outcome. The serum level of sLAG3 is positively correlated with patient prognosis. Conclusions: This study demonstrated that CHA injection in patients with recurrent high grade glioma, at the MTD of 5.5mg/kg, was safety and well tolerated with potential antitumor activity. Clinical trial information: NCT02245204.