Background Patients with relapsed unresectable osteosarcoma represents an unmet need, so active and safe systemic treatments are required. Fas cell surface death receptor and mammalian target of rapamycin pathways are implicated in progressing osteosarcoma, and we had preclinical and clinical experience with a scheme that targets both pathways. Therefore, we designed a phase II trial with gemcitabine plus rapamycin, to determine the efficacy and safety, in this subset of patients. Patients and methods A multicenter, single-arm phase II trial was sponsored by the Spanish Group for Research on Sarcoma. Osteosarcoma patients, relapsed or progressing after standard chemotherapy and unsuitable for metastasectomy received gemcitabine and rapamycin p.o. 5 mg/day except for the same day of gemcitabine administration, and the day before. The main end point was 4-month progression-free survival rate (PFSR), with the assumption that rates higher than 40% would be considered as an active regimen. Translational research aimed to correlate biomarkers with the clinical outcome. Results Thirty-five patients were enrolled and received at least one cycle. PFSR at 4 months was 44%, and after central radiologic assessment, 2 partial responses and 14 stabilizations (48.5%) were reported from 33 assessable patients. The most frequent grade 3-4 adverse events were: neutropenia (37%), thrombocytopenia (20%), anemia (23%), and fatigue (15%); however, only three patients had febrile neutropenia. Positive protein expression of RRM1 significantly correlated with worse PFS and overall survival, while positivity of P-ERK1/2 was correlated with significant better overall survival. Conclusion Gemcitabine plus sirolimus exhibits satisfactory antitumor activity and safety in this osteosarcoma population, exceeding the prespecified 40% of 4-month PFSR. The significant correlation of biomarkers with clinical outcome encourages further prospective investigation.

中文翻译：

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吉西他滨加西罗莫司治疗标准化疗后复发和进展的骨肉瘤患者：西班牙肉瘤研究小组 (GEIS) 的多中心、单臂 II 期试验。

背景 复发性不可切除骨肉瘤患者的需求未得到满足，因此需要积极和安全的全身治疗。Fas 细胞表面死亡受体和雷帕霉素通路的哺乳动物靶点与骨肉瘤的进展有关，我们在针对这两种通路的方案方面拥有临床前和临床经验。因此，我们设计了一项吉西他滨加雷帕霉素的 II 期试验，以确定这部分患者的疗效和安全性。患者和方法 西班牙肉瘤研究小组赞助了一项多中心、单臂 II 期试验。标准化疗后复发或进展且不适合转移瘤切除术的骨肉瘤患者接受吉西他滨和雷帕霉素口服 5 mg/天，吉西他滨给药当天和前一天除外。主要终点是 4 个月无进展生存率 (PFSR)，假设高于 40% 的无进展生存率将被视为有效方案。旨在将生物标志物与临床结果相关联的转化研究。结果 35 名患者入组并接受了至少一个周期。4 个月时的 PFSR 为 44%，在中央放射学评估后，33 名可评估患者报告了 2 次部分缓解和 14 次稳定（48.5%）。最常见的 3-4 级不良事件是：中性粒细胞减少 (37%)、血小板减少 (20%)、贫血 (23%) 和疲劳 (15%)；然而，只有三名患者出现发热性中性粒细胞减少症。RRM1 的阳性蛋白表达与较差的 PFS 和总体存活率显着相关，而 P-ERK1/2 的阳性与显着更好的总体存活率相关。结论 吉西他滨联合西罗莫司在该骨肉瘤人群中表现出令人满意的抗肿瘤活性和安全性，超过了预先设定的 4 个月 PFSR 的 40%。生物标志物与临床结果的显着相关性鼓励进一步的前瞻性研究。