AZD2281 vs AG014699

Hi


I'm currently on a clinical trial for tthe AG014699 version which is administered via a 30 min infusion over a 5 day period every 3rd week, whereas im aware that AZD2281 is taken orally twice a day continuously.


I was hoping you might be able to tell me if there is any differences between these 2 drugs.or whether they are the same drug  that are just administered in different ways.

Thanks

Anita

[Annekathryn Goodman, M.D.]

Dear Anita
I do not know the answer to this but you should ask your doctor who is administering this experimental drug.

here is one study on it:

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/m2 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/m2 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/m2. 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/m2 based on 74 -97% inhibition of PBL PARP activity. PK evaluation for AG-014699 alone after 2 - 12 mg/m2 shows mean terminal T = 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/m2 TMZ. Median tumor PARP inhibition at 5 hours was 90% (range 50 - 98%). Conclusions: Doses up to 12 mg/m2 AG-014699 and 200 mg/m2 TMZ are safe and significantly inhibit PBL and tumor PARP. One further dose level (AG-014699 18 mg/m2, TMZ 200 mg/m2) will be tested to maximize tumor PARP inhibition.

Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings.
Vol 23, No 16S (June 1 Supplement), 2005: 3065


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