Phase I clinical trial of a day-1,-3,-5 every 3 weeks schedule with titanocene dichloride (MKT 5) in patients with advanced cancer - A study of the phase I study group of the Association for Medical Oncology (AIO) of the German Cancer Society

Background: Titanocene dichloride (TD) is an organometallic compound with a ntiproliferative properties in vitro and promising antitumor activity in pr eclinical in vivo models. The drug interferes with DNA, blocks the S/G(2) p hase of the cell cycle and shows antiangiogenic properties. The purpose of this study was to determine the maximum tolerated dose (MTD) and the dose-l imiting toxicity (DLT) of a 'split' dose administration schedule (days 1, 3 , 5 q 3 weeks). Patients and Method: Patients with progressive advanced can cer and a creatinine clearance > 60 ml/ min qualified for a treatment with TD after standard therapies (radio-, chemo-, hormone therapy) failed. A tot al of 10 patients (4 females, 6 males) with a median age of 58 (range 49-68 ) years were treated with 80 mg/m(2) TD at days 1, 3 and 5 (repeated at day 22). The drug was administered as light-protected infusion within 1 h. Res ults: Significant side effects were as follows: nausea/vomiting, appetite l oss, renal toxicity (elevation of serum creatinine and proteinuria) and liv er toxicity (bilirubin and alkaline phosphatase elevation), but no myelosup pression. At the starting dose (3x80 = 240 mg/m(2)TD), renal (3 patients) o r liver toxicity (1 patient) of grade 3 was judged as DLT No further dose e scalation was possible. No objective tumor remission was observed. Conclusi on:The tolerability of TD cannot be improved by splitting the total dose in to three treatments every other day. Compared to previous phase I data usi ng a 3-weekly and a 1-weekly schedule, the 'split' dose administration allo wed no further increase of the total drug dose per treatment cycle. Thus, d ose intensification by alterations of the application mode does not seem to be possible.