Phase I and subsequent phase II study of filgrastim (r-met-HuG-CSF) and dose intensified cyclophosphamide plus epirubicin in patients with non-Hodgkin's lymphoma and advanced solid tumors

Background: To define a maximum tolerated dose (MTD) for the combination of epirubicin and cyclophosphamide with filgrastim (r-met-HuG-CSF) in patient s with advanced solid tumors and non-Hodgkin's lymphoma (NHL). Patients and methods: Thirty-five patients with advanced solid tumors were enrolled in stages I and II. Twenty-one patients were treated in stage I in sequential cohorts of at least three patients at increasing dosage levels of cyclophosphamide and epirubicin, for up to six cycles every 21 days. At the completion of stage I, a MTD for epirubicin was established. Fourteen p atients were treated in stage II, in cohorts of three or more. The epirubic in dose remained constant at the MTD dosage from stage I. Cyclophosphamide was further dose-escalated to establish its MTD. Twenty-one patients with p reviously untreated non-Hodgkin's lymphoma were treated in stage III with t he MTD established in the prior stages. Results: The MTD in stage I was epirubicin 150 mg/m(2) and cyclophosphamide 1500 mg/m(2) with cumulative neutropenia as the dose-limiting toxicity (DL T). Cumulative thrombocytopenia prevented further dose-escalation of cyclop hosphamide in stage II. The stage III regimen consisted of six, 21-day cycl es of epirubicin 150 mg/m(2), cyclophosphamide 1500 mg/m(2), vincristine 2 mg, and prednisolone 100 mg for five days with filgrastim support. Nineteen of twenty-one patients (90%) completed six cycles of treatment, eight (38% ) without dose reduction. Common toxicity criteria (CTC) grade 4 neutropeni a (neutrophil nadir < 0.5 x 10(9)/l) was documented in 85 of 118 cycles (72 %). Neutropenic fever was documented in 17 of 21 patients (81%) on at least one occasion. Severe thrombocytopenia (< 25 x 10(9)/l) was seen in fourtee n of 118 cycles (12%) and increased with cycle number. There was no signifi cant non-hematological toxicity. Conclusion: Significant dose-escalation of epirubicin and cyclophosphamide was possible with filgrastim support. The MTD achieved was approximately do uble that of standard-dose therapy. This study forms the basis of an ongoin g randomized study evaluating dose-intensification in intermediate grade NH L.