Abstract：
RRx-001 is a novel cysteine-targeted alkylating agent that releases nitric oxide (NO). The primary biological activities of this hybrid molecule include macrophage repolarizing and vascular normalization. The purpose of this clinical trial (ROCKET) (NCT02096354) was to compare the safety and efficacy of the combination therapy RRx-001 + irinotecan vs. regorafenib in third/fourth line colorectal cancer that previously received treatment with irinotecan.
A total of 34 patients were randomized (24 to RRx-001 + irinotecan (RxI) and 10 to single-agent regorafenib (RegI)) and were the basis for the intention-to-treat analysis (ITT, comprising all 34 patients). RRx-001 treatment was administered as an up-to-2-month \"primer\" followed by irinotecan for patients randomized to the RRx-001 arm (24). The efficacy and safety data are presented for the 34 patients in the (ITT) efficacy analysis. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly for up to 2 months, at which point RRx-001 was discontinued, followed by intravenous infusion of irinotecan at 180 mg/m2 on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m2 on day 1 in a 21-day cycle. There were 3 patients (3/24 = 12.5%) with prior single agent irinotecan on the RRx-001 randomized arm and 2 (2/10 = 20%) on the regorafenib randomized arm. Numerous patients had irinotecan combination therapies prior to randomized treatment. There were 15 patients on RRx-001 arm that received irinotecan post-RRx-001 in the randomized trial. There were 5 PRs on RRx-001 plus irinotecan leading to an overall response of 20.8% (5/24). There were 37.5% (9/24) of RRx-001 randomized patients with KRAS mutant type while 60% (6/10) regorafenib randomized patients were of KRAS type mutant. There were only 4 patients with available QOL and Edmonton Symptom Assessment System, an insufficient sample size to allow for any meaningful analysis.
Median patient follow-up was approximately 14.5 months (SD 4.5 months). Median overall survival was 8.6 months for RxI and 4.7 months for RegI. Median progression free survival was 6.1 months for RxI vs. 1.7 months for RegI (a statistically significant result, 2-sided log-rank test, P = .0030). The toxicity profile of RxI was substantially improved compared with RegI.
The results of this trial demonstrate improved efficacy of RxI compared with RegI in patients with metastatic colorectal cancer after previous treatment with irinotecan, and late-stage clinical development in this indication is planned on the strength of the observed \"signal\" accompanied by a sufficient safety profile.
A total of 34 patients were randomized (24 to RRx-001 + irinotecan (RxI) and 10 to single-agent regorafenib (RegI)) and were the basis for the intention-to-treat analysis (ITT, comprising all 34 patients). RRx-001 treatment was administered as an up-to-2-month \"primer\" followed by irinotecan for patients randomized to the RRx-001 arm (24). The efficacy and safety data are presented for the 34 patients in the (ITT) efficacy analysis. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly for up to 2 months, at which point RRx-001 was discontinued, followed by intravenous infusion of irinotecan at 180 mg/m2 on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m2 on day 1 in a 21-day cycle. There were 3 patients (3/24 = 12.5%) with prior single agent irinotecan on the RRx-001 randomized arm and 2 (2/10 = 20%) on the regorafenib randomized arm. Numerous patients had irinotecan combination therapies prior to randomized treatment. There were 15 patients on RRx-001 arm that received irinotecan post-RRx-001 in the randomized trial. There were 5 PRs on RRx-001 plus irinotecan leading to an overall response of 20.8% (5/24). There were 37.5% (9/24) of RRx-001 randomized patients with KRAS mutant type while 60% (6/10) regorafenib randomized patients were of KRAS type mutant. There were only 4 patients with available QOL and Edmonton Symptom Assessment System, an insufficient sample size to allow for any meaningful analysis.
Median patient follow-up was approximately 14.5 months (SD 4.5 months). Median overall survival was 8.6 months for RxI and 4.7 months for RegI. Median progression free survival was 6.1 months for RxI vs. 1.7 months for RegI (a statistically significant result, 2-sided log-rank test, P = .0030). The toxicity profile of RxI was substantially improved compared with RegI.
The results of this trial demonstrate improved efficacy of RxI compared with RegI in patients with metastatic colorectal cancer after previous treatment with irinotecan, and late-stage clinical development in this indication is planned on the strength of the observed \"signal\" accompanied by a sufficient safety profile.
摘要：
背景：RRx-001是一种新型的半胱氨酸靶向的烷化剂，可释放一氧化氮（NO）。该杂合分子的主要生物活性包括巨噬细胞复极化和血管正常化。本临床试验（ROCKET）（NCT02096354）的目的是比较RRx-001+伊立替康与联合治疗的安全性和有效性。regorafenib在以前接受伊立替康治疗的第三/四线结直肠癌中。
方法：共有34例患者被随机分配（24例接受RRx-001伊立替康（RxI）和10例接受单药瑞戈非尼（RegI）），并且是意向治疗分析的基础（ITT，包括所有34名患者)。对于随机分配到RRx-001组的患者，RRx-001治疗作为长达2个月的“引物”进行，然后是伊立替康（24）。在(ITT)疗效分析中提供了34名患者的疗效和安全性数据。治疗包括静脉内给予RRx-001，每周一次4mg，持续2个月。此时RRx-001已停产，随后在21天周期的第1天静脉输注伊立替康180mg/m2与160毫克口服瑞戈非尼每日3/4周，随后在进展，如果适用，在21天的周期中，在第1天通过伊立替康180毫克/平方米。在RRx-001随机分组中，有3例（3/24=12.5％）先前使用伊立替康的患者，在regorafenib随机分组中，有2例（2/10=20％）。许多患者在随机治疗之前接受了伊立替康联合治疗。在随机试验中，RRx-001组中有15名患者在RRx-001后接受伊立替康。RRx-001加伊立替康的5个PR导致20.8%的总体反应(5/24)。有37.5％（9/24）的RRx-001随机患者为KRAS突变型，而60％（6/10）的瑞戈非尼随机患者为KRAS突变型。只有4名患者有可用的生活质量和埃德蒙顿症状评估系统，样本量不足，无法进行任何有意义的分析。
结果：患者的中位随访时间约为14.5个月（SD4.5个月）。RxI的中位总生存期为8.6个月，RegI的中位总生存期为4.7个月。RxI与RxI的中位无进展生存期为6.1个月RegI为1.7个月(具有统计学意义的结果，双侧对数秩检验，P=.0030）。与RegI相比,RxI的毒性谱显著改善。
结论：该试验的结果表明，在先前接受伊立替康治疗后，与RegI相比，RxI对转移性结直肠癌患者的疗效有所改善。在此适应症的后期临床开发是根据观察到的“信号”强度以及足够的安全性进行计划的。
方法：共有34例患者被随机分配（24例接受RRx-001伊立替康（RxI）和10例接受单药瑞戈非尼（RegI）），并且是意向治疗分析的基础（ITT，包括所有34名患者)。对于随机分配到RRx-001组的患者，RRx-001治疗作为长达2个月的“引物”进行，然后是伊立替康（24）。在(ITT)疗效分析中提供了34名患者的疗效和安全性数据。治疗包括静脉内给予RRx-001，每周一次4mg，持续2个月。此时RRx-001已停产，随后在21天周期的第1天静脉输注伊立替康180mg/m2与160毫克口服瑞戈非尼每日3/4周，随后在进展，如果适用，在21天的周期中，在第1天通过伊立替康180毫克/平方米。在RRx-001随机分组中，有3例（3/24=12.5％）先前使用伊立替康的患者，在regorafenib随机分组中，有2例（2/10=20％）。许多患者在随机治疗之前接受了伊立替康联合治疗。在随机试验中，RRx-001组中有15名患者在RRx-001后接受伊立替康。RRx-001加伊立替康的5个PR导致20.8%的总体反应(5/24)。有37.5％（9/24）的RRx-001随机患者为KRAS突变型，而60％（6/10）的瑞戈非尼随机患者为KRAS突变型。只有4名患者有可用的生活质量和埃德蒙顿症状评估系统，样本量不足，无法进行任何有意义的分析。
结果：患者的中位随访时间约为14.5个月（SD4.5个月）。RxI的中位总生存期为8.6个月，RegI的中位总生存期为4.7个月。RxI与RxI的中位无进展生存期为6.1个月RegI为1.7个月(具有统计学意义的结果，双侧对数秩检验，P=.0030）。与RegI相比,RxI的毒性谱显著改善。
结论：该试验的结果表明，在先前接受伊立替康治疗后，与RegI相比，RxI对转移性结直肠癌患者的疗效有所改善。在此适应症的后期临床开发是根据观察到的“信号”强度以及足够的安全性进行计划的。
