Phase I study to determine the safety of oral administration of TAS-102 on a twice daily (BID) schedule for five days a week (wk) followed by two days rest for two wks, every (Q) four wks in patients (pts) with metastatic breast cancer (MBC)

Abstract

10576 Background: TAS-102 is an oral combination of 5-trifluorothymidine (FTD) and a thymidine phosphorylase (TP) inhibitor. FTD is an antineoplastic antimetabolite that causes DNA-fragmentation after passive incorporation into DNA. The TP inhibitor prevents degradation of FTD when orally administered. This agent is active against many tumor cell lines including breast cancer. In animal studies, the use of divided daily dosing of TAS-102 has resulted in increased FTD incorporation into tumor DNA. This study was conducted to determine the phase II dose and the dose limiting toxicity (DLT) of TAS-102 in pts with solid tumors/MBC. Methods: Pts with MBC refractory to standard therapy (tx) or for whom no standard tx existed were eligible to participate on study. Pts with either measurable or evaluable MBC were enrolled at an initial dose level of 80 mg/m²/day given in divided doses BID days 1–5 of 7 days for 2 wks q 4 wks with standard 3+3 design. DLT was defined as any of the following in cycle 1 a. ≥ grade (gr) 3 non-hematologic toxicity (excluding nausea/vomiting); b. inability to take ≥ 75% of planned study dose per cycle; c. gr 4 granulocytopenia (GCP) lasting ≥ 3 days or febrile ≥ gr 3 GCP of any duration or gr 4 thrombocytopenia (TCP); d. > 1 week delay in administration of the next scheduled dose. Evaluation of response was conducted every 8 wks. The recommended phase II dose was defined as the highest dose level that did not cause a DLT in 1/3 or more pts in that cohort. Results: 19 pts with MBC (median age: 56; median prior tx: 4) received tx with TAS-102. A median of 2 cycles were received (range 1–24) with one pt still on study. The initial starting dose resulted in DLT in 2/3 pts. Two additional dose levels were studied. The main cycle 1 toxicities were gr 3–4 GCP in 11/19 pts; gr 4 TCP in 1/19 pt. Other grade 3–4 toxicities were rare with minimal alopecia. The recommended phase II dose was determined to be 50 mg/m²/day given in divided doses BID days 1–5 of 7 days for 2 wks q 4 wks. Clinical activity was seen including prolonged disease control (> 12 weeks) in 7 pts. Conclusions: TAS-102 given BID as described is an active agent against heavily pretreated MBC with primarily hematologic toxicity. [Table: see text]