Chiappori Alberto A, Eckhardt S Gail, Bukowski Ronald, Sullivan Daniel M, Ikeda Minoru, Yano Yoshitaka, Yamada-Sawada Takuko, Kambayashi Yoshikaze, Tanaka Kazushige, Javle Milind M, Mekhail Tarek, O'bryant Cindy L, Creaven Patrick J
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Clin Cancer Res. 2007 Apr 1;13(7):2091-9. doi: 10.1158/1078-0432.CCR-06-1586.
Matrix metalloproteinases (MMP) play a fundamental role in cancer development and progression. S-3304 is a potent, orally active, noncytotoxic inhibitor of MMPs, primarily MMP-2 and MMP-9, that prolongs survival in mice xenografts and is well tolerated in healthy volunteers.
The aims of this phase I clinical trial were to determine the maximum tolerated dose, dose-limiting toxicities, pharmacokinetic profile, and intratumoral MMP inhibitory activity of single-agent S-3304 in advanced and refractory solid tumors. MMP activity was determined by film in situ zymography (FIZ). Patients had tumor biopsies before and after S-3304 administration and were also evaluated for response and survival.
Four dose levels were explored [DL1-DL4 or 800, 1,600, 2,400, and 3200 mg twice daily (BID), respectively], and 32 patients were enrolled. Toxicities were mostly gastrointestinal. The maximum tolerated dose was not reached, but dose escalations beyond DL4 were impractical (number of capsules needed). S-3304 steady-state concentrations were reached by day 8, and day 1 mean C(max) and AUC(0-8) increases were less than dose proportional. After S-3304 administration, 17 of 18 patients experienced inhibition of MMP activity by FIZ. Strong mean inhibition of MMP activity was observed in DL1 to DL3. The negative mean inhibitory activity calculated for DL4 was due to one patient with a 397% MMP activity increase.
S-3304 is safe, well tolerated, and achieves plasma concentrations above those required to inhibit MMP-2 and MMP-9. Its intratumoral MMP inhibitory activity has been shown using FIZ, which is useful as a biomarker with this and other MMP inhibitors.
基质金属蛋白酶（MMP）在癌症的发生和发展中起重要作用。S-3304是一种强效、口服活性、无细胞毒性的MMP抑制剂，主要抑制MMP-2和MMP-9，可延长小鼠异种移植瘤的生存期，且在健康志愿者中耐受性良好。
本I期临床试验的目的是确定单药S-3304在晚期难治性实体瘤中的最大耐受剂量、剂量限制性毒性、药代动力学特征以及瘤内MMP抑制活性。通过膜原位酶谱法（FIZ）测定MMP活性。患者在服用S-3304前后进行肿瘤活检，并评估疗效和生存期。
探索了四个剂量水平[DL1-DL4，分别为每日两次（BID）800、1600、2400和3200mg]，共入组32例患者。毒性主要为胃肠道反应。未达到最大耐受剂量，但超过DL4进行剂量递增不切实际（所需胶囊数量过多）。第8天达到S-3304稳态浓度，第1天的平均C(max)和AUC(0-8)增加与剂量不成比例。服用S-3304后，18例患者中有17例通过FIZ检测到MMP活性受到抑制。在DL1至DL3观察到较强的平均MMP活性抑制。DL4计算得出的平均抑制活性为阴性是由于1例患者的MMP活性增加了397%。
S-3304安全、耐受性良好，可达到抑制MMP-2和MMP-9所需的血浆浓度以上。已通过FIZ证明其瘤内MMP抑制活性，FIZ可作为该药物及其他MMP抑制剂的生物标志物。
