OBJECTIVES Second-line chemotherapy is not a standard of care in patients with malignant pleural mesothelioma (MPM) that progresses after first-line treatment with cisplatin and pemetrexed. In pre-clinical models, the combination of gemcitabine (GEM) and imatinib mesylate (IM), compared with GEM alone, led to a further tumor growth inhibition and improved survival. This phase II study evaluates the antitumor activity of a combination of IM and GEM in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by immunohistochemistry (IHC). PATIENTS AND METHODS GEM (1000 mg/m2) was given on days 3 and 10; IM (400 mg) was taken orally on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was the 3-month progression-free survival (PFS) rate. The study follows the optimal two-stage design of Simon. A 3-month PFS target of 75 % was required. With a probability error α = 10 % and a power of 80 %, the calculated sample size was 22 patients. In particular, in the first step, six out of nine patients and globally 14/22 patients free from progressive disease at 3 months were required. Secondary endpoints included response rate, duration of response, toxicity and overall survival (OS). RESULTS In total, 23 patients were enrolled (ECOG PS 0-1/2: 9/13; one previous line/≥two previous lines: 10/13). Partial response was achieved in four patients (17.4 %) and stable disease in 11 (47.8 %) with a disease control rate of 65.3 %. After a median follow-up of 34.5 months, median PFS and OS were 2.8 and 5.7 months, respectively. The 3-month PFS rate was 39.1 % (9/23 patients). All-grade drug-related adverse events occurred in 17 (73.9 %) patients. Grade 3 treatment-related adverse events were observed in four (17 %) patients. CONCLUSIONS The combination of IM and GEM is well tolerated in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by IHC, but it does not show a significant PFS benefit.

中文翻译：

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培美曲塞预处理的恶性胸膜间皮瘤患者吉西他滨联合甲磺酸伊马替尼的II期研究。

目的二线化疗不是恶性胸膜间皮瘤（MPM）患者的标准治疗方法，该患者在顺铂和培美曲塞一线治疗后进展。在临床前模型中，与单独的GEM相比，吉西他滨（GEM）和甲磺酸伊马替尼（IM）的组合可进一步抑制肿瘤生长并提高生存率。这项II期研究通过免疫组织化学（IHC）评价了IM和GEM联合治疗对表达PDGFR-β和/或cKIT的铂金属-培美曲塞预处理的MPM患者的抗肿瘤活性。患者和方法在第3天和第10天给予GEM（1000 mg / m2）；在21天周期的第1-5天和8-12天口服IM（400 mg）。主要终点是3个月无进展生存率（PFS）。该研究遵循西蒙的最佳两阶段设计。需要3个月的PFS目标为75％。概率误差α= 10％，功效为80％，计算出的样本量为22名患者。尤其是，第一步需要在9例患者中有6例，在14个月中总共有3/3例没有进展性疾病的患者。次要终点包括缓解率，缓解持续时间，毒性和总生存期（OS）。结果总共招募了23例患者（ECOG PS 0-1 / 2：9/13；前一条线/≥两条前线：10/13）。4例患者（17.4％）达到部分缓解，11例疾病（47.8％）稳定，疾病控制率为65.3％。中位随访34.5个月后，中位PFS和OS分别为2.8和5.7个月。3个月的PFS率为39.1％（9/23例患者）。17名患者（73.9％）发生了所有等级的药物相关不良事件。在四名（17％）患者中观察到了与3级治疗相关的不良事件。结论在IHC表达PDGFR-β和/或cKIT的铂培美曲塞预处理的MPM患者中，IM和GEM的组合耐受性良好，但未显示出明显的PFS获益。