GANNET53 Part II: A European Phase I/II Trial of the HSP90 Inhibitor Ganetespib in High-Grade Platinum-Resistant Ovarian Cancer-A Study of the GANNET53 Consortium.

The open-label, randomized phase II GANNET53 trial is the first to evaluate the HSP90 inhibitor ganetespib (G) with paclitaxel (P) in platinum-resistant epithelial ovarian cancer (EUDRACT 2013-003868-31; EU FP7 #602602).

开放标签、随机的II期GANNET53试验是首个评估HSP90抑制剂ganetespib（G）与紫杉醇（P）联合治疗铂类耐药性上皮性卵巢癌的临床试验（EUDRACT 2013-003868-31; EU FP7 #602602）。

patients_and_methods

Patients were randomized 2:1 to receive G + P or P alone until progression.

患者按2:1的比例随机接受G+P联合治疗或单独P治疗，直至疾病进展。

Primary endpoints were progression-free survival(PFS) and PFS rate at 6 months.

主要终点是无进展生存期（PFS）和6个月时的PFS率。

Exploratory endpoints were biomarkers based on p53 and HSP90.

探索性终点是基于p53和HSP90的生物标志物。

Results

A total of 133 patients were enrolled.

共有133名患者被纳入研究。

The median PFS was 3.5 (G + P) and 5.3 months (P) (HR = 1.3; 95% confidence interval, 0.897-1.895; P = 0.16), and PFS rates at 6 months were 22% (G + P) and 33% (P).

中位无进展生存期为3.5个月(G + P组)和5.3个月(P组) (风险比HR = 1.3; 95% 置信区间, 0.897-1.895; P = 0.16)，6个月无进展生存率分别为22% (G + P组)和33% (P组)。

No significant differences were found in overall survival, objective response rate, and post-progression PFS between arms.

两组间总生存期、客观缓解率和疾病进展后的无进展生存期没有发现显著差异。

The most frequent adverse events were diarrhea (79% vs. 26%), anemia (46% vs. 51%), nausea (41% vs. 40%), and peripheral neuropathy (36% vs. 47%).

最常见的不良事件是腹泻（79%对比26%）、贫血（46%对比51%）、恶心（41%对比40%）和周围神经病变（36%对比47%）。

Serious adverse events were more common in G + P (39.5% vs. 23.3%).

严重的不良事件在G+P组更为常见（39.5%对比23.3%）。

Gastrointestinal perforation was a new safety finding.

胃肠道穿孔是一项新的安全发现。

Despite a high TP53 mutation frequency, HSP90-p53 complexes were detected in only 39.6% of the cases and were also detected stably during treatment.

尽管TP53突变频率高，但在39.6%的病例中检测到HSP90-p53复合体，并且在治疗期间也稳定检测到。

In vitro, no synergistic effects of G + P were observed, and mutant p53 depletion did not sensitize ovarian cancer cells to treatment.

体外实验中，未观察到G+P的协同效应，且突变型p53的耗竭并未使卵巢癌细胞对治疗敏感。

Conclusions

Although no major safety findings were observed, G + P did not lead to survival benefit.

尽管未观察到主要的安全性问题，但G+P并未带来生存益处。

Our companion diagnostic program confirmed that G + P do not favorably cooperate in killing ovarian cancer cells.

我们的伴随诊断项目确认了G和P在杀伤卵巢癌细胞方面并不具有协同作用。