Background

CEND-1 is a novel cyclic peptide that targets αV integrins and neuropilin-1 and enhances tumour delivery of co-administered anticancer drugs. We investigated the safety, tolerability, and biological activity of CEND-1 in patients with metastatic pancreatic ductal adenocarcinoma in combination with nab-paclitaxel and gemcitabine.

Methods

This open-label, multicentre, phase 1 study, conducted at three hospitals in Australia, enrolled participants aged 18 years or older with histologically confirmed metastatic pancreatic ductal adenocarcinoma who had one or more lesions measurable on MRI or CT, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a life expectancy of at least 3 months. Exclusion criteria included previous chemotherapy and brain metastases or other malignancy (unless receiving curative intent). There was no randomisation or masking. CEND-1 monotherapy was given as an intravenous fluid bolus on day 1 of a run-in phase of 7 days (0·2–3·2 mg/kg) followed by CEND-1 plus intravenous gemcitabine (1000 mg/m²) and nab-paclitaxel (125 mg/m²) on days 1, 8, and 15 of 28-day treatment cycles until disease progression. The primary safety endpoints were incidence, severity, and duration of treatment-emergent and treatment-related adverse events; overall survival; and clinical laboratory results, which were all assessed in the safety population. This study is registered with ClinicalTrials.gov, NCT03517176, and the Australian New Zealand Clinical Trials Registry, ACTRN12618000804280.

Findings

Between Aug 13, 2018, and Nov 30, 2019, 31 patients were enrolled (eight in the dose-escalation phase [cohort 1a] and 23 in the expansion phase [cohort 1b]). Two patients were excluded from the efficacy population. No CEND-1 dose-limiting toxicities were observed in the safety population (n=31). The most common grade 3 or 4 events were neutropenia (17 [55%] patients), anaemia (eight [26%]), leukopenia (five [16%]), and pulmonary embolism (four [13%]). Serious adverse events occurred in 22 (71%) patients, mostly related to disease progression. Ten deaths occurred during the study due to progression of metastatic pancreatic cancer (n=9) and a left middle cerebral artery stroke (n=1). In the efficacy population (n=29), 17 (59%) patients had an objective response, including one complete response and 16 partial responses. After a median follow-up of 26 months (IQR 24–30), median overall survival was 13·2 months (95% CI 9·7–22·5).

Interpretation

CEND-1 with nab-paclitaxel and gemcitabine has an acceptable safety profile, with no dose-limiting toxicities and encouraging activity. Adverse events were generally consistent with those seen with nab-paclitaxel and gemcitabine. Further randomised trials to determine the efficacy of CEND-1 are warranted.

Funding

DrugCendR Australia Pty.

中文翻译：

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双 αV-整合素和神经毡蛋白-1 靶向肽 CEND-1 加上白蛋白结合型紫杉醇和吉西他滨治疗转移性胰腺导管腺癌：一项首次人体、开放标签、多中心、1 期研究

 背景

CEND-1 是一种新型环肽，以 αV 整合素和神经毡蛋白-1 为靶点，可增强联合抗癌药物的肿瘤递送。我们研究了 CEND-1 联合白蛋白结合型紫杉醇和吉西他滨治疗转移性胰腺导管腺癌患者的安全性、耐受性和生物活性。

 方法

这项开放标签、多中心、一期研究在澳大利亚三家医院进行，招募了年龄在 18 岁或以上、经组织学证实患有转移性胰腺导管腺癌的参与者，这些参与者具有 MRI 或 CT（东部肿瘤合作组的一项表现）可测量的一个或多个病变状态得分为 0 或 1，预期寿命至少为 3 个月。排除标准包括既往化疗和脑转移或其他恶性肿瘤（除非接受治疗）。没有随机化或掩蔽。 CEND-1 单一疗法在 7 天磨合期的第 1 天以静脉推注形式给予 (0·2–3·2 mg/kg)，随后给予 CEND-1 加静脉注射吉西他滨 (1000 mg/m ² )和白蛋白结合型紫杉醇 (125 mg/m ² )，在 28 天治疗周期的第 1、8 和 15 天进行，直至疾病进展。主要安全终点是治疗中出现的和治疗相关的不良事件的发生率、严重程度和持续时间；总体生存率；和临床实验室结果，这些结果均在安全人群中进行了评估。本研究已在 ClinicalTrials.gov（NCT03517176）和澳大利亚新西兰临床试验注册中心（ACTRN12618000804280）注册。

 发现

2018年8月13日至2019年11月30日期间，共有31名患者入组（8名患者处于剂量递增阶段[队列1a]，23名患者处于扩展阶段[队列1b]）。两名患者被排除在有效人群之外。在安全人群中未观察到 CEND-1 剂量限制性毒性 (n=31)。最常见的 3 级或 4 级事件是中性粒细胞减少症（17 例 [55%] 患者）、贫血（8 例 [26%]）、白细胞减少症（5 例 [16%]）和肺栓塞（4 例 [13%]）。 22 名 (71%) 患者发生严重不良事件，大部分与疾病进展有关。研究期间，由于转移性胰腺癌进展（n=9）和左大脑中动脉卒中（n=1），发生了 10 例死亡。在有效人群 (n=29) 中，17 名 (59%) 患者出现客观缓解，包括 1 名完全缓解和 16 名部分缓解。中位随访 26 个月 (IQR 24–30) 后，中位总生存期为 13·2 个月 (95% CI 9·7–22·5)。

 解释

CEND-1 联合白蛋白结合型紫杉醇和吉西他滨具有可接受的安全性，没有剂量限制性毒性且活性令人鼓舞。不良事件通常与白蛋白结合型紫杉醇和吉西他滨所见的不良事件一致。有必要进行进一步的随机试验来确定 CEND-1 的功效。

 资金

 DrugCendR 澳大利亚有限公司