OBJECTIVES Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1-3 inhibitor, as a second or third-line treatment. MATERIALS AND METHODS We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon's two-stage design: 26 patients would be recruited to the first stage and more than 7 (27 %) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients. RESULTS 3 of 24 patients (12 %) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes. CONCLUSIONS The FGFR 1-3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy.

中文翻译：

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单一口服FGF抑制剂AZD4547作为恶性胸膜间皮瘤的二线或三线治疗的II期试验。

目的目前，对于一线化疗后复发的恶性胸膜间皮瘤（MPM）患者，尚无最佳的挽救疗法。遵循针对恶性间皮瘤靶向成纤维细胞生长因子受体（FGFR）信号的强大的临床前理论，我们进行了一项II期研究，评估口服酪氨酸多激酶FGFR 1-3抑制剂AZD4547作为第二种还是第三种的疗效在线治疗。材料和方法我们对一线或二线全身化疗后确诊，可测量的MPM和放射学进展的合格患者进行了AZD4547的单中心，开放标签，单臂II期研究。患者以每周3周的周期接受连续两次，每日两次的口服AZD4547。主要终点是6个月无进展生存期（PFS6）。根据修改后的RECIST间皮瘤标准（mRECIST），每6周用CT扫描评估反应，并评估毒性。该研究采用了西蒙公司的两阶段设计：将26名患者招募到第一阶段，并且26名患者中有7名（27％）需要达到PFS6才能继续进入第二阶段，潜在的总队列数为55名患者。结果24例患者中有3例（12％）在6个月时无进展。因此，该研究符合停止标准，无论是否进一步招募和保证终止。最常见的毒性（所有级别）是高磷酸盐血症，口干症，粘膜炎，视网膜病变，消化不良和疲劳。在所有周期中，所有患者的最大毒性为2级或以下。肿瘤BAP1蛋白的丢失与临床结果之间没有关联。