Goffin John R, Anderson Ian C, Supko Jeffrey G, Eder Joseph Paul, Shapiro Geoffrey I, Lynch Thomas J, Shipp Margaret, Johnson Bruce E, Skarin Arthur T
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Clin Cancer Res. 2005 May 1;11(9):3417-24. doi: 10.1158/1078-0432.CCR-04-2144.
Marimastat is an orally bioavailable inhibitor of matrix metalloproteinases. A phase I study was initiated to determine whether conventional doses of carboplatin and paclitaxel are tolerated when combined with marimastat and to assess the influence of marimastat on paclitaxel pharmacokinetics.
Three dose levels were evaluated. Marimastat (10 or 20 mg oral administration b.i.d.) was administered continuously with paclitaxel (175 or 200 mg/m(2) as a 3-hour i.v. infusion) and carboplatin (at a dose providing an area under the free drug plasma concentration-time curve of 7 mg min/mL) administered each 3 weeks. Toxicity and response were evaluated throughout the intended four cycles of combined therapy. The plasma pharmacokinetics of paclitaxel was determined in each patient both without concurrent marimastat and after receiving marimastat for 1 week.
Twenty-two chemotherapy-naive patients with stage IIIb (27%) or stage IV (73%) non-small cell lung cancer were enrolled. Their median age was 56 years (range, 39-73 years), 50% were female, and their performance status (Eastern Cooperative Oncology Group) ranged from 0 to 2. Treatment was well tolerated, as 18 (82%) of the patients completed all four cycles of chemotherapy without dose-limiting toxicity. Grade 2 musculoskeletal toxicities were reported in 3 of 12 patients receiving marimastat (20 mg b.i.d.). Nine patients required dose reductions, predominantly related to low-grade myelosuppression. Partial responses occurred in 12 of 21 (57%) evaluable patients with disease stabilization in another 5 (19%). Marimastat had no effect on paclitaxel pharmacokinetics.
The administration of marimastat (10 mg b.i.d.) with paclitaxel (200 mg/m(2)) and carboplatin at an area under the free drug plasma concentration-time curve of 7 mg min/mL was well tolerated with no apparent pharmacokinetic interaction. Study of this drug combination in the adjuvant setting should be considered if tissue inhibition of matrix metalloproteinase activity can first be shown.
马立马司他是一种口服生物利用度良好的基质金属蛋白酶抑制剂。开展了一项I期研究，以确定常规剂量的卡铂和紫杉醇与马立马司他联合使用时是否可耐受，并评估马立马司他对紫杉醇药代动力学的影响。
评估了三个剂量水平。马立马司他（口服10或20 mg，每日两次）与紫杉醇（175或200 mg/m²，静脉输注3小时）持续联合给药，卡铂（剂量为使游离药物血浆浓度 - 时间曲线下面积达到7 mg·min/mL）每3周给药一次。在联合治疗预期的四个周期内评估毒性和反应。在每位患者未同时使用马立马司他时以及接受马立马司他1周后，均测定紫杉醇的血浆药代动力学。
招募了22例初治的IIIb期（27%）或IV期（73%）非小细胞肺癌患者。他们的中位年龄为56岁（范围39 - 73岁），50%为女性，其体能状态（东部肿瘤协作组）范围为0至2。治疗耐受性良好，因为18例（82%）患者完成了所有四个周期的化疗，无剂量限制性毒性。在接受马立马司他（20 mg，每日两次）的12例患者中有3例报告了2级肌肉骨骼毒性。9例患者需要降低剂量，主要与轻度骨髓抑制有关。21例可评估患者中有12例（57%）出现部分缓解，另有5例（19%）病情稳定。马立马司他对紫杉醇药代动力学无影响。
马立马司他（10 mg，每日两次）与紫杉醇（200 mg/m²）及游离药物血浆浓度 - 时间曲线下面积为7 mg·min/mL的卡铂联合给药耐受性良好，无明显药代动力学相互作用。如果首先能够证明对基质金属蛋白酶活性的组织抑制作用，则应考虑在辅助治疗中研究这种药物组合。
