C-1311, a novel inhibitor of FLT3 and topoisomerase II: A phase 1 trial of a once every three week schedule in patients with advanced solid tumors

Abstract

2576 Background: C-1311 (Symadex) is a lead compound in the novel class of imidazoacridinones, inhibitors of both topoisomerase II and certain receptor tyrosine kinases (RTK) including FLT3, being tested for the treatment of cancer and autoimmune diseases. This phase 1 trial assessed safety, determined the maximum tolerated dose (MTD) and recommended dose (RD) of C-1311 in patients (pts) with advanced solid tumors. Methods: Pts with tumors refractory to conventional therapy were enrolled. The dosing schedule was a 1-hr infusion daily for 5 consecutive days every 3 weeks (dx5), subsequently amended to once every 3 weeks (q3w). The maximum tolerated dose (MTD) is where 2 or more of at least 3 pts experience dose-limiting toxicity (DLT). The recommended dose (RD) is the dose level below the MTD. An expanded RD cohort of 9 pts was also evaluated. Systemic pharmacokinetics were assessed. Results: 36 pts were treated. No DLTs were observed in the first 5 single patient cohorts on a dx5 schedule at 6, 12, 24, 48 and 96 mg/m2/day. Subsequent pts were treated in 3+3 patient cohorts at 640, 850 and 1,100 mg/m2, and 950 mg/m², which was the MTD. All DLT were hematologic, reversible neutropenia and occasional thrombocytopenia. Grade 3 and 4 neutropenia was observed in 19% and 17% of pts in the first treatment cycle (no associated sepsis). No cumulative toxicity was observed. Nonhematologic treatment-related adverse events (AEs) were lethargy (75%), nausea (50%), vomiting (44%), neutropenia (36%), dizziness (31%) and fatigue and infusion site pain (22% each), with grade 3/4 AEs being lethargy, atypical pneumonia, and dyspnea in one patient (3%) each. No nonhematologic DLT or abnormal LVEF were observed. Partial response and stable disease (SD) were observed in 1 (3%) and 17 (47%) pts. Conclusions: C1311 is a novel imidazoacridinone targeting both topoisomerase II and FLT 3 family of RTK. The RD on a q3w schedule of 850 mg/m2 has acceptable safety. DLT is only reversible dose-related neutropenia. SD in heavily pretreated pts with sarcomas and epithelial malignancies suggests preliminary evidence of antitumor activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Xanthus Pharmaceuticals Xanthus Pharmaceuticals