A phase I study of high-dose BCNU, etoposide and escalating-dose thiotepa (BTE) with hematopoietic progenitor cell support in adults with recurrent and high-risk brain tumors

This phase I dose-escalation study was performed to determine the tolerabil ity of three-drug combination high-dose BCNU (B) (450 mg/m(2)), escalating- dose thiotepa (500-800 mg/m(2)) and etoposide (1200 mg/m(2)) in divided dos es over four days in 22 adults with malignant primary brain tumors. Patient s received G-CSF and hematopoeitic support with peripheral blood progenitor cells (PBPC) (n=18) or both PBPC and marrow (n=4). The maximum tolerated d ose of thiotepa with acceptable toxicity was determined as 800 mg/m(2). The 100-day mortality rate was 9% (2/22). Grade III/IV toxicities included muc ositis (71%), diarrhea (29%), nausea/vomiting (19%), and hepatic toxicity ( 14%). Neurological toxicities occurred in 24% and included seizures (two pa tients) and encephalopathy (three patients). Encephalopathy was transient i n two patients and progressive in one patient. All patients had neutropenic fever. Median time to engraftment with absolute neutrophil count (ANC) > 0 .5x10(9)/l was 10 days (range 8-30 days). Platelet engraftment > 20x10(9)/l occurred after 11 days (range 9-65 days). In the eighteen patients support ed solely with PBPC, there was a significant inverse correlation between CD 34(+) dose and days to ANC (rho=-0.78, p=0.001) and platelet engraftment (r ho=-0.76, p=0.002). Overall, 11% of evaluable patients (2/18) had a complet e response to BTE. Median time to tumor progression (TTP) was 9 months, wit h an overall median survival of 17 months. BCNU (450 mg/m(2)), thiotepa (80 0 mg/m(2)) and etoposide (1200 mg/m(2)) in divided doses over four days is a tolerable combination HDC regimen, the efficacy of which warrants further investigation in adults with optimally resected chemoresponsive brain tumo rs.