Randomized phase I and pharmacological study of weekly or 2-weekly gemcitabine and cisplatin in advanced non-small cell lung cancer

Abstract

Cisplatin (cis) and gemcitabine (gem) are cytotoxic drugs that have shown synergism in non-small cell lung cancer (NSCLC). The standard schedule doses gem weekly and cis once every 4 weeks. We believe that increasing the dose-intensity of cis could further optimize the efficacy of this combination in NSCLC. Therefore, we are performing a phase I/II trial with weekly or 2-weekly gem+cis to determine a schedule with the highest dose-intensity of both agents with manageable toxicity. A secondary objective is to study the pharmacokinetics of this combination. Patients with advanced disease are randomized to receive weekly or 2-weekly gem on day 1 plus cis on day 2. In the weekly scheme such a course is given in week 1, 2, 3, 5, 6 and 7, and in the 2 weekly scheme in week 1, 3, 5 and 7. The total dose-intensity of the two schedules is equal, which means that the doses per administration in the 2-weekly scheme are 50% higher than in the weekly scheme. Per cohort of six patients the dose is increased until the maximum-tolerated dose (MTD) is reached. Pharmacokinetics (PK) of gem, its deaminated metabolite dFdU, and its phosphorylated active metabolite dFdCTP are studied during course 1, and cis (total and free) PK in plasma as well as intrastrand Pt-GG and Pt-AG DNA-adducts in WBC are determined in weeks 1 and 3. As yet, 73 patients have been entered into the study (35/38 M/F; median age 53, range 34–76 years; median PS WHO 1, range 0–2) with stage IIIB (42%) and IV (58%) NSCLC. Doses were increased stepwise from 25 mg m−2 to 60 mg m−2 cis and 600 mg m−2 to 1000 mg m−2 gem in the weekly schedule. Further dose escalation in this scheme was hampered by the occurrence of dose-delays, caused by haematological toxicity (mainly neutropenia). On the 2-weekly schedule the starting dose was 37.5 mg m−2 cis and 900 mg m−2 gem and has been increased to 90 mg m−2 cis in combination with 1500 mg m−2 gem, which is most likely the MTD. On this schedule, dose-limiting toxicity consists of nausea, vomiting and ototoxicity. Other commonly observed side-effects are fatigue, constipation and neutropenia. Haematological toxicity has not exceeded CTC grade 3 in any patient. An interim response evaluation demonstrated partial remissions in 31% of patients. However, the response rate is strongly dependent on disease stage and clinical condition at study entry, and difficult to interpret in the mixed patient population in our trial. PK parameters for gem and cis in plasma were not different from literature data. An interaction was found between gem and the platinum-DNA adducts in WBC: when increasing the dose of gem, both types of adducts formed, Pt-GG– and Pt-AG, decreased. We have demonstrated that chemotherapy with gemcitabine in combination with cisplatin at an almost double dose-intensity than in the standard schedule, is feasible. The PK interaction of this combination is subject of further studies. Furthermore, we have recently continued this clinical trial investigating the reversed administration sequence.