First in human phase I trial of the PARP inhibitor AG-014699 with temozolomide (TMZ) in patients (pts) with advanced solid tumors.
Plummer R., Middleton M., Wilson R., Jones C., Evans J., Robson L., Steinfeldt H., Kaufman R., Reich S., Calvert AH.
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].