A Randomized, Double‐Blinded, Phase II Trial of Gemcitabine and Nab‐Paclitaxel Plus Apatorsen or Placebo in Patients with Metastatic Pancreatic Cancer: The RAINIER Trial

Abstract

Lessons Learned.

• The addition of the heat shock protein 27 (Hsp27)‐targeting antisense oligonucleotide, apatorsen, to a standard first‐line chemotherapy regimen did not result in improved survival in unselected patients with metastatic pancreatic cancer.

• Findings from this trial hint at the possible prognostic and predictive value of serum Hsp27 that may warrant further investigation.

Background.

This randomized, double‐blinded, phase II trial evaluated the efficacy of gemcitabine/nab‐paclitaxel plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 (Hsp27) mRNA, or placebo in patients with metastatic pancreatic cancer.

Methods.

Patients were randomized 1:1 to Arm A (gemcitabine/nab‐paclitaxel plus apatorsen) or Arm B (gemcitabine/nab‐paclitaxel plus placebo). Treatment was administered in 28‐day cycles, with restaging every 2 cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and on treatment. The primary endpoint was overall survival (OS).

Results.

One hundred thirty‐two patients were enrolled, 66 per arm. Cytopenias and fatigue were the most frequent grade 3/4 treatment‐related adverse events for both arms. Median progression‐free survival (PFS) and OS were 2.7 and 5.3 months, respectively, for arm A, and 3.8 and 6.9 months, respectively, for arm B. Objective response rate was 18% for both arms. Patients with high serum level of Hsp27 represented a poor‐prognosis subgroup who may have derived modest benefit from addition of apatorsen.

Conclusion.

Addition of apatorsen to chemotherapy does not improve outcomes in unselected patients with metastatic pancreatic cancer in the first‐line setting, although a trend toward prolonged PFS and OS in patients with high baseline serum Hsp27 suggests this therapy may warrant further evaluation in this subgroup.

Translated abstract

经验总结

• 在非经选转移性胰腺癌患者的标准一线化疗方案中添加靶向热休克蛋白27 (Hsp27) 的反义寡核苷酸apatorsen不会延长生存期。

•本试验的结果提示血清Hsp27可能具有预后和预测价值, 但需进行进一步研究。

摘要

背景. 本项随机、双盲、II期试验评价了吉西他滨/白蛋白结合型紫杉醇联合apatorsen[靶向热休克蛋白27 (Hsp27) mRNA的反义寡核苷酸]或安慰剂治疗转移性胰腺癌患者的效果。

方法. 患者按1:1的比例被随机分配进入A组（吉西他滨/白蛋白结合型紫杉醇联合apatorsen）或B组（吉西他滨/白蛋白结合型紫杉醇联合安慰剂）。治疗周期为28天, 每2个周期对疾病进行一次重新分期, 直至出现疾病进展或不可耐受的毒性。在基线期和治疗期间分析了血清Hsp27水平。主要终点为总生存期（OS）。

结果. 共入组了132例患者, 每组66例。血细胞减少和疲乏是两组中最常见的3/4级治疗相关不良事件。A组的中位无进展生存期（PFS）和OS分别为2.7和5.3个月；B组分别为3.8和6.9个月。两组的客观缓解率均为18%。Hsp27血清水平较高的患者代表可能已经从添加apatorsen中适度获益的预后不佳亚组。

结论. 在非经选转移性胰腺癌患者的一线化疗中添加apatorsen不会改善治疗结局, 但基线期血清Hsp27水平较高患者的PFS和OS延长的趋势表明可能需在该亚组中对这一疗法进行进一步研究。