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.

A Randomized, Double-Blinded, Phase II Trial of Carboplatin and Pemetrexed with or without Apatorsen (OGX-427) in Patients with Previously Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer: The SPRUCE Trial

“…Apatorsen, the Hsp27 inhibitor used in this study, has been added to several standard regimens and investigated in several cancer types. Randomized phase II studies in bladder and prostate cancer suggested a modest benefit , whereas no benefit was seen in combination with gemcitabine/nab‐paclitaxel in pancreatic cancer . Additional trials with several Hsp inhibitors are ongoing.…”

Targeting Heat Shock Protein 27 in Cancer: A Druggable Target for Cancer Treatment ?

“…toxicity [51]. However, clinical study reported that the treatment of OGX-427 to a standard chemotherapy regimen, did not result in increased survival in unselected patients with metastatic pancreatic cancer, but there was a trend toward prolonged progression-free survival and overall survival in patients with high baseline serum HSP27, suggesting that this therapy may warrant further evaluation in the subgroup [52].…”

Clinical Potential of Oligonucleotide Therapeutics against Pancreatic Cancer

“…A modified ASO that is complementary to Hsp27 (OGX-427) has been developed, showing inhibition of tumor progression and enhancement of gemcitabine's efficacy in pancreatic cancer [36]. Thereafter, a phase II trial of OGX-427 plus gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer was carried out and revealed that the addition of OGX-427 to chemotherapy had no improved effect in the first-line setting [37]. Thus, clinical trials of the ASO strategy, as a new therapy combined with conventional drugs for advanced states of pancreatic cancer, have not shown significant additional value for these patients, going against our expectations.…”