Phase I trial of weekly docetaxel(D) plus cisplatin(C) in the treatment of advanced non-small cell lung cancer(NSCLC) / 中国癌症杂志

ABSTRACT

Purpose:The phase I study was conducted to evaluate the maximum tolerated dose (MTD) and toxicity of weekly administered docetaxel combined with cisplatin in patients with non-small cell lung cancer ( NSCLC ). The other objective was to measure the pharmacokinetic/dynamics (PK/PD).Methods:In the dose escalation study, 15 patients with unresectable and metastatic untreated NSCLC with performance status(0-1) were enrolled. Escalating doses of D 25 mg/m 2 (30 mg/m 2, 35 mg/m 2, 40 mg/m 2) on day 1, 8, 15 were given as a 30 min iv infusions and C 75 mg/m 2 30 min iv infusion after D on day 1 and the cycle was repeated every 4 weeks. Blood samples were drawn on day 1 and 15 in the first cycle to measure the PK. Dose limiting toxicity(DLT) was based on Cycle 1 and defined as any Grade 3 non-hematologic toxicity not declining to Grade 2 or less within 4 days or any Grade 4 toxicity. Results:Chemotherapy was repeated for at least two cyc1es every 28 days. All patients were assessable for toxicities. Although grade 3/4 neutropenia occurred, there were no significant modifications of chemotherapy schedule. One patient developed an infection (DLT). Non-hematological toxicities, including nausea/vomiting, a1opecia, fluid intension and asthenia were tolerable. Based on these data, the MTD has not yet reached up to dose level of docetaxel of 40mg/m 2 weekly given in combination with cisplatin 75mg/m 2 every 4 weeks at the fixed dose. The exposure to docetaxel after Ⅳ administration on day 1 in combination with cisplatin and on day 15 without cisplatin , increased proportional to the dose for the range 25 to 40 mg/m 2, as measured by Cmax and AUC. No statistically significant difference between clearance values was shown for the 4 dose levels. The pharmacokinetics of docetaxel was not influenced by the coadministration of cisplatin on day 1 as compared to day 15, as the CmaxN, AUCN and CL were not statistically significantly different on both days. Fourteen patients were eva1uab1e for response, five cases achieved partial response, and thus the overall response was 35.7%. 1, 2, and 3 year survivals were 73%, 27%, and 20%, respectively. Weekly administration of docetaxel at 35mg/m 2 (days 1, 8, l5) combined with cisplatin 75mg/m 2 (day 1) is recommended for phase Ⅱ studies. Conclusions:Using the weekly schedule, toxicity was mainly manifested by non-hematologic profile and was well tolerated. A phase Ⅱ study is currently ongoing with docetaxel 35mg/m 2 as the suggested dosage.