Phase I study of escalating doses of edatrexate in combination with paclitaxel in patients with metastatic breast cancer

Motivated by the observation of preclinical synergy, a Phase I dose escalat ion study of edatrexate in combination with a 3-h paclitaxel infusion was p erformed in patients with advanced breast cancer to determine the maximum t olerated dose (MTD) of edatrexate and the toxicities associated with this c ombination and to report preliminary observations of efficacy with this nov el combination. Thirty-six patients were enrolled in this Phase I trial. Thirty-five eligib le patients were treated every 21 days in cohorts of at least three patient s and were assessable for toxicity. One patient was ineligible due to hyper bilirubinemia, Stepwise dose escalations of edatrexate were administered un til grade >3 nonhematological dose-limiting toxicities were reported. The i nitial dose level of edatrexate was 180 mg/m(2); subsequent cohorts were tr eated with escalating doses of edatrexate (210, 240, 270, 300, 350, and 400 mg/m(2)). Edatrexate was administered by i.v. infusion over 1 h, Paclitaxe l was administered 24 h later at a fixed dose of 175 mg/m(2) as a 3-h infus ion with standard dexamethasone, diphenhydramine, and cimetidine premedicat ion. The MTD of edatrexate was reached at the 350 mg/m(2) level in this study, G rade 3 diarrhea was seen in one patient at the 300 and 400 mg/m(2) dose lev els, requiring dose reductions. Two patients experienced grade 4 stomatitis at the 400 mg/m(2) dose level and also required dose reduction, establishi ng the MTD as 350 mg/m(2). Grade 3 nausea and vomiting were noted in two of three patients at the highest dose level. Of 35 patients, 4 patients repor ted grade 3 myalgias and 1 patient reported grade 3 neurosensory complaints , which were seen mostly at the 350 and 400 mg/m(2) dose levels; however, 1 patient reported grade 3 myalgias at 180 mg/m(2), No cumulative neurotoxic ity was observed, and no patient experienced an allergic reaction to paclit axel, In 23 patients with bidimensionally measurable disease, there were four com plete (17%) and seven partial responses, with an overall response rate of 4 8% (95% confidence interval, 27-69%), All of the responses were seen in pat ients who had not received prior chemotherapy for stage IV disease. The med ian duration of response was not assessable because many responding patient s went on to receive high-dose chemotherapy treatment with stem cell suppor t. The combination of edatrexate and paclitaxel for treatment of metastatic br east cancer is a feasible and safe regimen, The MTD of edatrexate was 350 m g/m(2) when combined with a 3-h infusion of paclitaxel (175 mg/m(2)) given 24 h later, Activity was noted even among patients who had relapsed shortly after receiving methotrexate- and/or doxorubicin-containing adjuvant regim ens. Additional studies evaluating the sequences and dosing schema for this combination are warranted to improve the response proportion and define th e duration of the response.