Phase I evaluation of a 24-h infusion of TAS-106 every 3 weeks (wks) in patients (pts) with solid tumors

2513 Background: The nucleoside 3’-C-ethynylcytidine (TAS-106) is metabolized in cancer cells to ethynylcytidine triphosphate (ECTP), an inhibitor of RNA polymerases I, II, and III. TAS-106 has potent anticancer activity in broad range of human tumor xenografts. In prior clinical studies, bolus intravenous (IV) TAS-106 caused reversible dose-limiting peripheral neuropathy and the recommended phase II dose (RP2D) was 4.21 mg/m2 every 3 wks. Myelosuppression, asthenia, and mild nausea and vomiting were also common. In rats, 24-h TAS-106 infusions are better tolerated with equivalent efficacy. Therefore, a Phase I study of 24-h infusions of TAS-106 was initiated. Methods: Escalating doses TAS-106 infused over 24-h every 3 wks were administered to cancer patients with pharmacokinetic (PK) monitoring during the initial cycle. Toxicity and response were assessed using NCI CTC (v2) grade (gr) and RECIST, respectively. Plasma and urine TAS-106 concentrations were monitored using LC/MS/MS methods. Results: Overall, 33 pts were treated at the following dose levels: 2.82 (4 pts), 3.5 (5 pts), 4.38 (6 pts), 5.48 (4 pts) 6.85 (6 pts) and 8.56 mg/m2 (8 pts). At 8.56 mg/m2, 2 of 5 pts experienced neutropenic DLTs (febrile neutropenia and gr 4 neutropenia lasting greater than or equal to 3 days) No neuropathy DLTs were observed. At 6.85 mg/m2, gr 3 peripheral neuropathy in cycle 1 was observed in 1 patient, but no other DLTs occurred in 5 patients. Other common drug related toxicities occurring in any cycle included gr 1–2 fatigue (13 pts), gr 3–4 neutropenia (10 pts), gr 1 hand/foot syndrome (9 pts), gr 2–3 anemia (9 pts) gr 1 rash/skin exfoliation (10 pts), and peripheral neuropathy gr 1–2 (5 pts). No objective responses were seen; although 3 pts with parotid, adenoid cystic, and breast cancers demonstrated stable disease for 5, 6, and 7 months, respectively. Plasma concentrations increased with increasing dose, and at 6.85 mg/m2, the Cmax was 77.4±7.3 ng/mL, AUC 1,892±54 ng·h/mL, CL 102±13 mL/h/kg, VDss 1.37±.05 L/kg, and t1/2 was 9.85±1.47 h. Over 48 h, 62.1% of the administered dose of TAS-106 was excreted into the urine. Conclusions: Compared with bolus dosing, 24-h infusions of TAS-106 are better tolerated with less peripheral neuropathy. The RP2D for TAS-106 infused over 24-h every 3 wks is 6.85 mg/m2. [Table: see text]