A PHASE-II AND PHARMACOKINETIC STUDY WITH ORAL PIRITREXIM FOR METASTATIC BREAST-CANCER

Piritrexim is a lipid-soluble antifolate which, like methotrexate, has a potent capacity to inhibit dihydrofolate reductase. We performed a multicentre phase 11 study with piritrexim in patients with locally ad vanced or metastatic breast cancer. Twenty-four patients of which sixt een had received prior chemotherapy, were initially treated with 25 mg piritrexim orally administered trice daily for four days, repeated we ekly, with provision for dose escalation or reduction according to obs erved toxicity. Of twenty-one patients evaluable for tumour response, one patient achieved a partial response which lasted for 24 weeks. Thr ee patients had stable disease during 12 weeks of treatment, seventeen had progressive disease. Piritrexim was generally well tolerated, in eighteen patients the dose could be escalated. Myelotoxicity was the m ost frequent observed toxicity of this piritrexim regimen. Leucopenia and thrombocytopenia grade 3/4 occurred in 38% of the patients sometim e during treatment. Pharmacokinetic analysis of piritrexim in three pa tients during the first treatment cycle, revelaed peak levels 1 to 2 h after an oral dose, with a trend towards a higher peak plasma levels and AUCs on the fourth dosing day compared with the first dosing day. In conclusion, orally administered piritrexim appears to be a regimen with little activity in patients with locally advanced or metastatic b reast carcinoma.