Evaluation of the safety of C-1311 administered in a phase 1 dose-escalation trial as a 1-hour infusion once every 3 weeks in patients with advanced solid tumors
12005 Background: C-1311 (Symadex) is the most active member of a new series of anti-cancer agents, the imidazoacridinones, specially designed compounds developed from research on the structure-activity relationships of existing cancer therapies. This clinical trial was designed to assess the safety profile of ascending doses of C-1311 and to determine the recommended dose when administered every 3 weeks (Q3W). Methods: Patients with advanced solid tumors refractory to conventional therapy were enrolled. The dose escalation scheme was divided into 2 phases with different schedules. Initially, C-1311 was given as a 1-hour daily infusion over 5 consecutive days. Following review of pre-clinical data, coupled with preliminary results of a parallel weekly study, a day 1 only schedule was explored. The maximum tolerated dose (MTD) is defined as the dose at which 2/3 or 2/6 pts experience a dose-limiting toxicity (DLT). The recommended dose (RD) is defined as the dose level below the MTD, confirmed by expansion of the RD cohort to 9 pts. Results: The first 5 patients were treated at doubling doses of 6, 12, 24, 48 and 96 mg/m2 on a schedule of 1-hour daily infusions over 5 consecutive days, repeated every 3 weeks; no DLTs were seen. The 6th pt received the same total dose as the 5th (480 mg/m2) but on day 1 only, following which a modified Fibonacci design with cohorts of 3 pts and 33% dose increments was utilized. Subsequently, pts received C-1311 at doses of 640 mg/m2 (3 pts), 850 mg/m2 (3 pts) and 1100 mg/m2 (5 pts); 2/5 pts treated at 1100 mg/m2 experienced an identical DLT (grade 4 neutropenia for ≥7 days with grade 4 thrombocytopenia), defining this as the MTD. The 850 mg/m2 cohort was expanded to confirm this as the RD. Neutropenia, thrombocytopenia, anemia and fatigue have been reported as drug-related grade 3 or 4 adverse events (AEs). Grade 1 or 2 AEs most commonly described as drug-related are fatigue, nausea, vomiting and diarrhea. Stable disease was observed in two patients with advanced malignancy. A pt had a stable disease over 8 cycles and one over 6 cycles. Plasma drug concentrations are linear and proportional to dose. Conclusions: A C-1311 dose of 850 mg/m2 administered once every 3 weeks offers a predictable and tolerable safety profile. [Table: see text]