Department of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Department of Medical Oncology I, 'Montabone' Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Italy.
Department of Medical Oncology I, 'Montabone' Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Italy.
Ann Oncol. 2010 Jun;21(6):1315-1322. doi: 10.1093/annonc/mdp504. Epub 2009 Nov 9.
The additive cytotoxicity in vitro prompted a clinical study evaluating the non-prodrug rapamycin analogue ridaforolimus (AP23573; MK-8669; formerly deforolimus) administered i.v. combined with paclitaxel (PTX; Taxol).
Patients with taxane-sensitive solid tumors were eligible. The main dose escalation foresaw 50% ridaforolimus increments from 25 mg with a fixed PTX dose of 80 mg/m(2), both given weekly 3 weeks in a 4-week cycle. Collateral levels with a lower dose of either drug were planned upon achievement of the maximum tolerated dose in the main escalation. Pharmacodynamic studies in plasma, peripheral blood mononuclear cells (PBMCs) and skin biopsies and pharmacokinetic (PK) interaction studies at cycles 1 and 2 were carried out.
Two recommended doses were determined: 37.5 mg ridaforolimus/60 mg/m(2) PTX and 12.5 mg/80 mg/m(2). Most frequent toxic effects were mouth sores (79%), anemia (79%), fatigue (59%), neutropenia (55%) and dermatitis (48%). Two partial responses were observed in pharyngeal squamous cell and pancreatic carcinoma. Eight patients achieved stable disease > or =4 months. No drug interaction emerged from PK studies. Decrease of eukaryotic initiation factor 4E-binding protein1 (4E-BP1) phosphorylation was shown in PBMCs. Similar inhibition of phosphorylation of 4E-BP1 and mitogen-activated protein kinase was present in reparative epidermis and vascular tissues, respectively.
Potential antiangiogenic effects and encouraging antitumor activity justify further development of the combination.
体外的附加细胞毒性促使进行了一项临床研究，评估静脉注射施用的非前药雷帕霉素类似物 ridaforolimus（AP23573；MK-8669；以前称为 deforolimus）与紫杉醇（PTX；Taxol）联合用药的效果。
有紫杉烷类敏感的实体瘤的患者符合条件。主要剂量递增方案设想雷帕霉素的剂量从 25 毫克增加 50%，同时固定紫杉醇剂量为 80 毫克/平方米，两者每周一次，每 3 周一个 4 周的周期。在主递增中达到最大耐受剂量后，计划使用药物的较低剂量作为旁系水平。在第 1 和第 2 周期进行了血浆、外周血单核细胞（PBMC）和皮肤活检的药效学研究以及药代动力学（PK）相互作用研究。
确定了两个推荐剂量：37.5 毫克 ridaforolimus/60 毫克/平方米 PTX 和 12.5 毫克/80 毫克/平方米。最常见的毒性作用是口腔溃疡（79%）、贫血（79%）、疲劳（59%）、中性粒细胞减少症（55%）和皮炎（48%）。在咽鳞癌和胰腺癌中观察到 2 例部分缓解。8 例患者达到>或=4 个月的稳定疾病。PK 研究未显示药物相互作用。在 PBMC 中显示出真核起始因子 4E 结合蛋白 1（4E-BP1）磷酸化的减少。在修复性表皮和血管组织中分别观察到 4E-BP1 和丝裂原活化蛋白激酶磷酸化的相似抑制。
潜在的抗血管生成作用和令人鼓舞的抗肿瘤活性证明了该联合用药的进一步开发是合理的。
