Phase I-II parallel study of docetaxel on a bimonthly schedule in refractory metastatic breast carcinoma

The 3-week schedule with docetaxel (DTC) 75-100 mg/2 is associated with severe neutropenia, gastro-intestinal side-effects and fluid retention in a significant proportion of patients, which may be of concern in more elderly or poor performance status patients. A phase I-II trial was carried out to test the feasibility and the activity of a new bimonthly schedule of DCT.

The trial included a phase I study which aimed at the identification of dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of DCT on a bimonthly schedule. The first group of three patients received DCT 40 mg/m2, and in absence of DLT, DCT dosage was escalated by 10 mg/m2/cycle until DLT was reached. In the phase II study, patients were randomized to receive: (a) standard 3-weekly DCT at the dose of 75 mg/m2 (calibration arm); or (b) bimonthly schedule with DCT at the dose recommended in the phase I study. All patients were pretreated with chemotherapy, mostly anthracycline-based regimens, for advanced/metastatic disease. Analysis of response rates, toxicity, and dose-intensity were the main aims of the study.

The DLT was represented by severe myelosuppression which was recorded in all patients treated at 70 mg/m2 dose level. Therefore, the MTD was 60 mg/m2 on a bimonthly schedule. However, the dose recommended for the phase II trial was 50 mg/m2, because no difference in delivered dose-intesity was seen between the 50 and 60 mg/m2 dose levels, and the latter dosage was still associated with grade 3 neutropenia in most patients. The parallel phase II study showed that the bimonthly schedule of DCT (50 mg/m2) allows to deliver the same dose-intensity of DCT 75 mg/m2 every 3 weeks. Grade 3-4 side-effects were rather infrequent in patients treated with the bimonthly schedule. Overall response rate (ORR) was 41 and 44% for the DCT 50 mg/m2 bimonthly and the DCT 75 mg/m2 every 3 weeks, respectively.

Data achieved in the phase I part of the study showed that DCT 50 mg/m2 every 15 days is the recommended dose for phase II studies, while results achieved in the phase II trial suggest that DCT 50 mg/m2 in a bimonthly schedule is active as second-line chemotherapy for MBC being able to induce an ORR in the range reported for DCT 75-100 mg/m2 every 3 weeks. The bimonthly schedule is, however, associated with relatively low toxicity. This characteristic may render the bimonthly schedule particularly attractive for future phase II trials of DCT in combination with other antineoplastic agents.