AE-941

Purpose: The best phase II design and endpoint for growth inhibitory agents is controversial. We simulated phase II trials by resampling patients from a positive (sorafenib vs. placebo; TARGET) and a negative (AE941 vs. placebo) phase III trial in metastatic renal cancer to compare the ability of various designs and endpoints to predict the known results.Experimental Design: A total of 770 and 259 patients from TARGET and the AE 941 trial, respectively, were resampled (5,000 replicates) to simulate phase II trials with α = 0.10 (one-sided). Designs/endpoints: single arm, two-stage with response rate (RR) by Response Evaluation Criteria in Solid Tumors (RECIST; 37 patients); and randomized, two arm (20–35 patients per arm) with RR by RECIST, mean log ratio of tumor sizes (log ratio), progression-free survival (PFS) rate at 90 days (PFS-90), and overall PFS.Results: Single-arm trials were positive with RR by RECIST in 55% and 1% of replications for sorafenib and AE 941, respectively. Randomized trials versus placebo with 20 patients per arm were positive with RR by RECIST in 55% and 7%, log ratio in 88% and 25%, PFS-90 in 64% and 15%, and overall PFS in 69% and 9% of replications for sorafenib and AE 941, respectively.Conclusions: Compared with the single-arm design and the randomized design comparing PFS, the randomized phase II design with the log ratio endpoint has greater power to predict the positive phase III result of sorafenib in renal cancer, but a higher false positive rate for the negative phase III result of AE 941. Clin Cancer Res; 18(8); 2309–15. ©2012 AACR.

To evaluate the protective role of AE-941, a matrix metalloproteinase (MMP) inhibitor, on ulcerative colitis (UC) in rats.

Sprague Dawley (SD) rats were randomly divided into three groups: a control group, an AE-941 treatment group, and an UC model group. Rats were sacrificed on days 7, 21, or 56 following administration of treatment by enema and the disease activity index (DAI), colonic mucosa damage index (CMDI) and colonic expression of MMP-2 and MMP-9 were assessed.

DAI and CDMI scores in the UC model group increased significantly compared to the control group at all timepoints (P < 0.001), and also increased significantly at the 21- and 56-d timepoints compared to the AE-941-treated group (DAI: 21- and 56-d = 2.09 ± 0.25, 1.52 ± 0.30 vs 1.55 ± 0.28, 0.59 ± 0.19, respectively, P = 0.040 and 0.007, CMDI: 21- and 56-d = 3.03 ± 0.42, 1.60 ± 0.35 vs 2.08 ± 0.46, 0.86 ± 0.37, respectively, P = 0.040 and 0.005). Furthermore, the colonic expression of MMP-2 and MMP-9 in the UC model group increased significantly compared to the control group (P < 0.001), and also increased compared to the AE-941-treated group on the 21- and 56-d timepoints (MMP-2: 21- and 56-d = 0.6048 ± 0.0522, 0.4163 ± 0.0330 vs 0.3983 ± 0.0218, 0.1093 ± 0.0072, respectively, P = 0.010; MMP-9: 21- and 56-d = 0.6873 ± 0.0472, 0.4328 ± 0.0257 vs 0.5179 ± 0.0305, 0.2673 ± 0.0210, respectively, P = 0.010 and 0.040).

Expression of MMP-2 and MMP-9 increased significantly in rats with UC. AE-941 can reduce colonic mucosal damage by downregulating the expression of MMP-2 and MMP-9.