Background

Napabucasin is an oral NAD(P)H:quinone oxidoreductase 1 bioactivatable agent that generates reactive oxygen species, is hypothesised to affect multiple oncogenic cellular pathways, including STAT-3, and is expected to result in cancer cell death. This phase I study investigated the safety, tolerability, and pharmacokinetics of napabucasin co-administered with fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) chemotherapy plus bevacizumab in Japanese patients with metastatic colorectal cancer (CRC).

Methods

Patients with histologically confirmed unresectable stage IV CRC received oral napabucasin 240 mg twice daily (BID). Intravenous FOLFIRI and bevacizumab therapy was initiated on day 3 at approved doses. Unacceptable toxicity was evaluated over the first 30 days of treatment, after which treatment continued in 14-day cycles until toxicity or disease progression. Endpoints included safety, pharmacokinetics, and tumour response based on RECIST v1.1.

Results

Four patients received treatment; three were evaluable during the unacceptable toxicity period. All four patients experienced diarrhoea and decreased appetite (considered napabucasin-related in four and two patients, respectively), and three patients experienced neutrophil count decreased. No unacceptable toxicity was reported during the 30-day evaluation period. No grade 4 events, deaths, or serious adverse events were reported. The addition of FOLFIRI and bevacizumab to napabucasin did not significantly change the pharmacokinetic profile of napabucasin; however, results were variable among patients. The best overall response was stable disease in two patients (50.0%).

Conclusions

Napabucasin 240 mg BID in combination with FOLFIRI and bevacizumab was tolerated, with a manageable safety profile in Japanese patients with metastatic CRC.

中文翻译：

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Napabucasin 联合 FOLFIRI + 贝伐单抗治疗日本转移性结直肠癌患者的 I 期研究

背景

Napabucasin 是一种口服 NAD(P)H:quinone oxidoreductase 1 生物活化剂，可产生活性氧，据推测会影响多种致癌细胞途径，包括 STAT-3，并预计会导致癌细胞死亡。这项 I 期研究调查了萘帕布卡星与氟尿嘧啶、L-亚叶酸和伊立替康 (FOLFIRI) 化疗联合贝伐单抗在日本转移性结直肠癌 (CRC) 患者中的安全性、耐受性和药代动力学。

方法

组织学证实不可切除的 IV 期 CRC 患者每天两次口服萘巴布卡辛 240 mg (BID)。在第 3 天以批准的剂量开始静脉内 FOLFIRI 和贝伐单抗治疗。在治疗的前 30 天内评估了不可接受的毒性，之后以 14 天的周期继续治疗，直到毒性或疾病进展。终点包括基于 RECIST v1.1 的安全性、药代动力学和肿瘤反应。

结果

4名患者接受了治疗；三个在不可接受的毒性期间是可评估的。所有 4 名患者均出现腹泻和食欲下降（分别认为 4 名和 2 名患者与萘帕布卡星相关），3 名患者出现中性粒细胞计数下降。在 30 天的评估期间没有报告不可接受的毒性。未报告 4 级事件、死亡或严重不良事件。Napabucasin 中加入 FOLFIRI 和贝伐单抗并未显着改变 Napabucasin 的药代动力学特征；然而，结果在患者之间存在差异。最好的总体反应是两名患者（50.0%）的疾病稳定。

结论

Napabucasin 240 mg BID 联合 FOLFIRI 和贝伐单抗是耐受的，在日本转移性 CRC 患者中具有可控的安全性。