PHASE-I STUDY OF MITOXANTRONE, METHOTREXATE AND MITOMYCIN WITH GRANULOCYTE-COLONY-STIMULATING FACTOR (FILGRASTIM) IN PATIENTS WITH ADVANCEDBREAST-CANCER

The combination of mitozantrone, methotrexate and mitomycin (3M) gives a response rate of around 50% in patients with advanced breast cancer . The predominant toxicity is haematological. In this study, previousl y untreated patients were given 3M with increasing doses of mitozantro ne (7-14 mg m(-2)) with recombinant human granulocyte colony-stimulati ng factor (metHuG-CSF) (filgrastim) to prevent marrow toxicity. Doses administered were 7 mg m(-2) mitomycin i.v. 6 weekly, methotrexate i.v . 35 mg m(-2) (maximum 50 mg) 3 weekly and mitozantrone i.v. 3 weekly as follows: 7 mg m(-2), six patients (group 1); 10 mg m(-2), six patie nts (group 2); 12 mg m(-2), six patients (group 3); 14 mg m(-2), six p atients (group 4); all on day 1 for six cycles at the assigned dose. A ll patients received filgrastim (Amgen 0.3 mg ml(-1)) at a dose of 5 m u g kg(-1) subcutaneously daily on days 4-17 of each cycle. All treatm ent was given on an out-patient basis. A total of 24 patients were ent ered into the study. The median age was 63 years (range 48-75). ECOG p erformance status was 0 in ten, 1 in 11 patients and 2 in three patien ts. Locoregional disease alone was present in seven patients. The rema inder had one or more sites of metastases. The actual dose administere d to the 24 patients was as follows. The six patients in group 1 all c ompleted six courses of treatment as per protocol. In group 2, three p atients completed six courses, two stopped because of toxicity after o ne and four courses and one had progressive disease after one course. In group 3, three patients completed and three stopped early because o f progressive disease. In group 4, two patients completed, one progres sed after four courses and three responding patients stopped treatment because of toxicity. The maximum tolerated dose of mitozantrone in th e 3M combination was 12 mg m(-2). The use of filgrastim with increasin g doses of chemotherapy prevents neutropenia, but other toxicities, na mely thrombocytopenia and lethargy, then become dose limiting.