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3065 Background: AG-014699 inhibits poly(ADP-ribose) polymerase (PARP) is a key enzyme in DNA repair. AG-014699 sensitizes cancer cells to DNA damaging drugs such as TMZ. AG-014699 is the first PARP inhibitor to be evaluated in cancer patients. METHODS: In part 1 of the study, pts with solid tumors received AG-014699 + TMZ daily x 5 every 28 days. TMZ dose was half of standard (100 mg/m(2) po) and AG-014699 (30 min infusion) was escalated up to the PARP-inhibitory dose (PID) as determined by PARP activity in peripheral blood lymphocytes (PBLs). We defined PID as maximal (at least >50%) reduction in PARP activity 24 hr after AG-014699. In part 2, AG-014699 dose was fixed at PID and TMZ was escalated to maximum tolerated dose or 200 mg/m(2) in metastatic melanoma pts. Endpoints included safety, efficacy, PK and tumor PARP activity (obligatory in part 2). Overall objective based on xenograft data was to achieve > 40% PARP inhibition in tumor. RESULTS: 27 pts enrolled, safety data available on first 18. In part 1, AG-014699 dose levels in 18 pts were 1, 2, 4, 8 and 12 mg/m(2). No dose-limiting toxicity (DLT) was observed. All related events were grade (gr) 1/2, except 1 case each of gr 3 infection, fatigue, low phosphate and lymphopenia. PID was 12 mg/m(2) based on 74 -97% inhibition of PBL PARP activity. PK evaluation for AG-014699 alone after 2 - 12 mg/m(2) shows mean terminal T[Formula: see text] = 7.4 - 11.7 hr, clearance = 25 L/hr, and linear dose proportionality for AUC and Cmax. AG-014699 did not affect TMZ PK compared to historical data. Two durable partial responses (15+, 9+ mo) occurred (GIST, melanoma). In part 2, no DLT was seen in 9 pts up to 200 mg/m(2) TMZ. Median tumor PARP inhibition at 5 hours was 90% (range 50 - 98%). CONCLUSIONS: Doses up to 12 mg/m(2) AG-014699 and 200 mg/m(2) TMZ are safe and significantly inhibit PBL and tumor PARP. One further dose level (AG-014699 18 mg/m(2), TMZ 200 mg/m(2)) will be tested to maximize tumor PARP inhibition. [Table: see text].

Type

Journal article

Journal

J Clin Oncol

Publication Date

06/2005

Volume

23