Departments of Medicine and Health Studies, University of Chicago, Chicago, Illinois, USA.
Clin Cancer Res. 2012 Apr 15;18(8):2309-15. doi: 10.1158/1078-0432.CCR-11-1815. Epub 2012 Jan 27.
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.
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.
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.
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.
生长抑制因子的最佳 II 期设计和终点仍存在争议。我们通过从转移性肾细胞癌的一项阳性（索拉非尼对比安慰剂；TARGET）和一项阴性（AE941 对比安慰剂）III 期试验中重新抽样患者来模拟 II 期试验，比较各种设计和终点预测已知结果的能力。
从 TARGET 和 AE 941 试验中分别重新抽取了 770 例和 259 例患者（5000 次重复），以模拟 II 期试验，α=0.10（单侧）。设计/终点：单臂，两阶段，以实体瘤反应评估标准（RECIST）的缓解率（RR）（37 例）；以及随机、两臂（每臂 20-35 例），以 RECIST、肿瘤大小的平均对数比（log 比）、90 天无进展生存率（PFS-90）和总 PFS 的 RR。
RR 为 RECIST 的单臂试验在索拉非尼和 AE 941 的 55%和 1%的重复中为阳性。RR 为 RECIST 的随机试验与安慰剂相比，每臂 20 例在索拉非尼和 AE 941 的 55%和 7%、log 比的 88%和 25%、PFS-90 的 64%和 15%以及总 PFS 的 69%和 9%的重复中为阳性。
与单臂设计和比较 PFS 的随机设计相比，具有 log 比终点的随机 II 期设计预测索拉非尼在肾细胞癌中的阳性 III 期结果的能力更强，但对 AE 941 的阴性 III 期结果的假阳性率更高。
