Phase I clinical trial of XK469 in patients with chemo-refractory solid tumors

Abstract

2020 Background: XK469 is a member of the quinoxaline family of antitumor agents. Based on encouraging pre-clinical data, a phase I trial was conducted to determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD). Methods: We used a 2B accelerated titration (AT) schema with drug administered as a 5- minute IV infusion days 1–5 every 21-days. Starting dose was 9 mg/m2. Results: 19 patients (18 evaluable) (median age of 57 years, median performance status of 1) were enrolled. 14/ 19 patients were heavily pretreated receiving > 3 previous chemotherapies and 10/ 19 received prior radiation therapy. At 260mg/m2/day, 1/ 6 patients experienced a DLT- grade 4 neutropenia. The following non- DLT's (grade 2 or higher) were observed: grade 3 neutropenia and thrombocytopenia (1 patient), grade 2 fatigue (1 patient) and grade 2 alopecia (1 patient). GI toxicity was mild and limited to grade 1 nausea (3 patients) and grade 1 vomiting (1 patient). At dose level 12 (346 mg/m2/day), 2/ 2 patients experienced DLT's with one episode of febrile neutropenia and one grade 3 infection. The projected MTD is 260mg/m2/day. XK469 peak plasma levels and systemic exposure were proportional to dose from 9 to 346 mg/m2/day indicating that the drug exhibits linear pharmacokinetics. However, secondary peaks in the PK profiles and a rapid decline in drug level from 23 to 24 hours occurred in some patients. Drug infusion in the afternoon followed by dense sampling of levels during the elimination phase confirmed the hypothesis that the drug was being sequestered in the biliary system resulting in fluctuating drug levels. An in vitro prediction model for MTD that uses drug sensitivity of CFU-GM successfully predicted the MTD and individual patient risk for neutropenia. To date, there have been no responses to therapy. Conclusions: The 2B AT design proved efficient, successfully identifying MTD with only 19 patients despite 12 dose escalations. Traditional PK sampling designs were inadequate to describe XK469 disposition. Stem cell assays can be used to predict MTD and individual patients' neutropenic risk. No significant financial relationships to disclose.